U.S. patent number 7,834,014 [Application Number 10/552,304] was granted by the patent office on 2010-11-16 for a.sub.2a adenosine receptor antagonists.
This patent grant is currently assigned to Biogen Idec MA Inc.. Invention is credited to Gnanasambandam Kumaravel, Hairuo Peng, Russell C. Petter, Gang Yao.
United States Patent |
7,834,014 |
Peng , et al. |
November 16, 2010 |
A.sub.2a adenosine receptor antagonists
Abstract
The invention is based on the discovery that compounds of
formula (I) possess unexpectedly high affinity for the A.sub.2a
adenosine receptor, and can be useful as antagonists thereof for
preventing and/or treating numerous diseases, including Parkinson's
disease. In one embodiment, the invention features a compound of
formula (I). ##STR00001##
Inventors: |
Peng; Hairuo (Chestnut Hill,
MA), Yao; Gang (Sudbury, MA), Petter; Russell C.
(Stow, MA), Kumaravel; Gnanasambandam (Westford, MA) |
Assignee: |
Biogen Idec MA Inc. (Cambridge,
MA)
|
Family
ID: |
33299825 |
Appl.
No.: |
10/552,304 |
Filed: |
April 9, 2004 |
PCT
Filed: |
April 09, 2004 |
PCT No.: |
PCT/US2004/011009 |
371(c)(1),(2),(4) Date: |
July 26, 2006 |
PCT
Pub. No.: |
WO2004/092173 |
PCT
Pub. Date: |
October 28, 2004 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20070173505 A1 |
Jul 26, 2007 |
|
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
60461484 |
Apr 9, 2003 |
|
|
|
|
Current U.S.
Class: |
514/246; 544/207;
544/209; 544/212 |
Current CPC
Class: |
A61P
25/16 (20180101); A61P 25/28 (20180101); C07D
519/00 (20130101); A61P 25/24 (20180101); A61P
25/06 (20180101) |
Current International
Class: |
C07D
487/04 (20060101); C07D 403/06 (20060101); C07D
403/14 (20060101); C07D 403/04 (20060101); A61K
31/53 (20060101); A61P 25/16 (20060101) |
Field of
Search: |
;544/207,209,212
;514/246 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
0390112 |
|
Oct 1990 |
|
EP |
|
0459702 |
|
Dec 1991 |
|
EP |
|
0496617 |
|
Jul 1992 |
|
EP |
|
0515107 |
|
Nov 1992 |
|
EP |
|
0666079 |
|
Aug 1995 |
|
EP |
|
0667349 |
|
Aug 1995 |
|
EP |
|
0976753 |
|
Feb 2000 |
|
EP |
|
0976755 |
|
Feb 2000 |
|
EP |
|
0992510 |
|
Apr 2000 |
|
EP |
|
1221444 |
|
Jan 2001 |
|
EP |
|
1116722 |
|
Jul 2001 |
|
EP |
|
1300147 |
|
Apr 2003 |
|
EP |
|
223066 |
|
May 1974 |
|
FR |
|
56131586 |
|
Oct 1981 |
|
JP |
|
56131587 |
|
Oct 1981 |
|
JP |
|
59062595 |
|
Apr 1984 |
|
JP |
|
60140335 |
|
Jul 1985 |
|
JP |
|
04036284 |
|
Feb 1992 |
|
JP |
|
WO9320078 |
|
Oct 1993 |
|
WO |
|
WO9413643 |
|
Jun 1994 |
|
WO |
|
WO9413677 |
|
Jun 1994 |
|
WO |
|
WO9417803 |
|
Aug 1994 |
|
WO |
|
WO9713676 |
|
Apr 1997 |
|
WO |
|
WO9901439 |
|
Jan 1999 |
|
WO |
|
WO9901454 |
|
Jan 1999 |
|
WO |
|
WO9943678 |
|
Feb 1999 |
|
WO |
|
WO9921617 |
|
May 1999 |
|
WO |
|
WO9940091 |
|
Aug 1999 |
|
WO |
|
WO9948903 |
|
Sep 1999 |
|
WO |
|
WO9962518 |
|
Dec 1999 |
|
WO |
|
WO0017201 |
|
Mar 2000 |
|
WO |
|
WO0061586 |
|
Oct 2000 |
|
WO |
|
WO0102400 |
|
Jan 2001 |
|
WO |
|
WO0102409 |
|
Jan 2001 |
|
WO |
|
WO0162233 |
|
Aug 2001 |
|
WO |
|
WO03020723 |
|
Mar 2003 |
|
WO |
|
WO03048163 |
|
Jun 2003 |
|
WO |
|
WO03068776 |
|
Aug 2003 |
|
WO |
|
WO2004029056 |
|
Apr 2004 |
|
WO |
|
Other References
Baraldi et al., European Journal of Medicinal Chemistry 38:
367-382, 2003. cited by examiner .
Koretskaya et al., Khim.-Farm. Zh. I (1968) 2(6) 5-12. cited by
other .
Mamaev et al., Getertsikl, Soedin, (1971) 7, 535. cited by other
.
Pendergast et al., J. Chem. Soc. Perkin. Trans. (1973) 1,
2759-2763. cited by other .
Machon et al., J. Pharmacol. Pharm. (1976) 28, 511. cited by other
.
Higashino et al., Chem Pharm Bull 24, 238-52 (1976). cited by other
.
Higashino et al., Chem Pharm Bull 24, 3120-34 (1976). cited by
other .
Hayashi et al., Yakugaku Zasshi 98, 891 (1978) Abstract. cited by
other .
Robev et al., Dokl. Bolg. Akad. Nauk. (1978) 31; 1131-1134. cited
by other .
Higashino et al., Chem. Pharm. Bull. (1979) 27, 2431. cited by
other .
Higashino et al., Chem. Pharm. Bull. (1979) 27, 3176. cited by
other .
Higashino et al., Fukusokan Kagaku Toronkai Koen Yoshishu, 12th,
1979, 171-5 (Japanese language Conference Report). cited by other
.
Press et al., J. Org. Chem. 48, 4605 (1983). cited by other .
Schechter et al (1985) J Clin Pharmacol 25, 276. cited by other
.
Higashino et al., Chem Pharm Bull 33, 950 (1985). cited by other
.
Bruns et al., (1986) Mol. Pharmacol. 29: 331-346. cited by other
.
Higashino et al., Chem Pharm Bull 34, 4352 (1986). cited by other
.
Higashino et al., Chem Pharm Bull 34, 4569 (1986). cited by other
.
Molina et al., Tetrahedron Letters (1987) 28, 4451-4454. cited by
other .
Higashino et al., Chem Pharm Bull 35, 4078 (1987). cited by other
.
Jaskolski et al., Acta Crystallogr Sect. C, (1987) C43, 2110-2113.
cited by other .
Molina et al., J. Org. Chem., (1988) 53, 4653-63. cited by other
.
Miyashita et al., Chem Pharm Bull 38, 230(1990). cited by other
.
Hamamichi et al., J. Heterocycl. Chem (1990) 31, 321. cited by
other .
Hamamichi et al., J. Heterocycl. Chem (1990) 27, 835. cited by
other .
Skalski et al., Can. J. Chem (1990) 68, 2164-2170. cited by other
.
Jacobsen et al., J. Med. Chem. (1992) 35(3), 407-423. cited by
other .
Chemical Abstracts, V. 118, No. 3 (1993) Abstract # 22077 Suzuki,
Hitomi et al (J. Org. Chem (1993) 58(1) 241-4). cited by other
.
Chemical Abstracts, V. 121, No. 9 (1994) Abstract # 108677 Bouillon
et al (Heterocycles (1994) 37(2) 915-32). cited by other .
Gunderson, Tetrahedron Lett (1994) 35, 3155. cited by other .
Colotta et al., Eur. J. Jed. Chem. (1995) 30(2), 133-139. cited by
other .
Gundersen et al., Tetrahedron Letters (1995) 36(11), 1945-1948.
cited by other .
Stevenson et al., Tetrahedron Lett. (1996) 37, 8375-8378. cited by
other .
Langli et al., Tetrahedron, vol. 52, Issue 15, Apr. 8, 1996, pp.
5625-5638. cited by other .
Bertorelli et al (1996) Drug Development Research 37, Issue 2 , pp.
65-72. cited by other .
Prassad et al., Tetrahedron (1997) 53, 7237-7254. cited by other
.
Chebib et al., Bioorganic & Med. Chem Lett (1997) 5(2) 311-322.
cited by other .
Biraldi et al., J. Med. Chem. (1998) 41, 2126-2133. cited by other
.
Francis et al., J. Med. Chem. (1998) 31, 1014-1020. cited by other
.
Monopoli et al. (1998) J Pharmacol Exp Ther 285 (1): 9. cited by
other .
Kim et al., Arch. Pharmacal. Res. (1998) 21, 458-464. cited by
other .
Molina et al., J. Org. Chem. (1998) 53, 4653-4663. cited by other
.
Suzuki et al., Chem Pharm Bull 46, 199 (1998). cited by other .
Monopoli et al (1998) NeuroReport 9, 3955-3959. cited by other
.
Strappaghetti et al, Eur. J. Med. Chem (1998) 33, 501-508. cited by
other .
Chorvat et al., J. Med. Chem. (1999) 42(5), 833-848. cited by other
.
Betti et al., Eur. J. Med Chem (1999) 34(10) 867-875. cited by
other .
Cocuzza et al., Bioorganic & Med. Chem Lett (1999) 9(7)
1063-1066. cited by other .
Fredholm et al., (1999) Pharmacol Rev. 51, 83-133. cited by other
.
Kopf et al. (1999) Psychopharmacol., 146, 214-219. cited by other
.
Li et al (1999) Experimental Eye Research 68, 9-17. cited by other
.
Svenningsson et al (1999) Progress in Neurobiology 59, 355-396.
cited by other .
Alarcon et al, Tetrahedron Lett (2000) 41, 7211-7215. cited by
other .
Alarcon et al, Bioorg Med Chem Lett (2001) 11, 1855-1858. cited by
other .
Stone et al., (2001) Drug Development Research 52, 323. cited by
other .
Scammell et al., (2001) Neuroscience 107, 653. cited by other .
El Yacoubi et al., (2001) British Journal of Pharmacology 134,
68-77. cited by other .
Kase (2001) Bioscience, Biotechnology, and Biochemistry 65,
1447-1457. cited by other .
Behan et al., (2002) British Journal of Pharmacology (2002) 135,
1435-1442. cited by other .
Ikeda et al (2002) J Neurochem. 80, 262-70. cited by other .
Bastia et al., (2002) Neuroscience Letters 328, 241-244. cited by
other .
Hauser et al (2003) Neurology 61 297. cited by other .
Urade et al (2003) Neurology 2003;61:S94-S96. cited by other .
Varani et al. (2003) FASEB J. 17, 2148-2150. cited by other .
Dall'lgna et al., (2003) Br J Pharmacol 138: 1207-1209. cited by
other .
Chase et al., (2003) Neurology 2003;61:S107-S111. cited by other
.
Bara-Jimenez et al., Neurology 2003 61: 293-296. cited by other
.
Bailey et al. J. Neurosci. 22 (21): 9210-9220. cited by
other.
|
Primary Examiner: Balasubramanian; Venkataraman
Attorney, Agent or Firm: Lando & Anastasi, LLP
Parent Case Text
This application is 371 of PCT/US04/11009, filed Apr. 9, 2004,
which claims benefit of U.S. Provisional Application No.
60/461,484, filed on Apr. 9, 2003.
Claims
What is claimed is:
1. A compound of the following formula: ##STR00013## or a
pharmaceutically acceptable salt or N-oxide thereof; wherein A is
an aryl or heteroaryl; each of B, B.sup.1, and B.sup.2 is N; each
of R.sup.2 and R.sup.3 is independently hydrogen, alkyl,
cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, or heteroaralkyl; X.sup.1 is a bond
or C.sub.1-6 alkylene, C.sub.2-6 alkenylene, or C.sub.2-6
alkynylene, each of which being optionally interrupted by or linked
terminally to --O--, --S--, or --N(R.sup.2)--; X.sup.2 is a bond,
C.sub.1-6 alkylene, C.sub.2-6 alkenylene, or C.sub.2-6 alkynylene;
L is a linker selected from the group consisting of: ##STR00014##
wherein: each of R' and R'' is independently hydrogen, alkyl,
alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo,
thioxo, cyano, guanadino, amidino, carboxy, sulfo, sulfoxy,
mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl,
aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino,
alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl,
sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy,
cycloalkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy,
heterocycloalkylsulfanyl, aryl, aryloxy, arylsulfanyl, aroyl,
heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl; X is
--C(R.sup.2)(R.sup.3)--, --N(R.sup.2)--, --O--, or --S--; each of
p, p1 and p2 is independently 0-2; each of q1 and q2 is
independently 0-2; each of m1 and m2 is independently 0-2; each of
r and r1 is independently is 1-2; and r2 is 0-1; Y is
--C(R.sup.2)(R.sup.3)--, --N(R''')--, --O--, --S--, --SO--,
--SO.sub.2--, --CO--, --CO.sub.2--, or a bond where R''' is
hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,
cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclyl, or
heterocyclylalkyl; and R.sup.1 is hydrogen, alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,
cycloalkenylalkyl, aryl, aralkyl, heterocyclyl, or
heterocyclylalkyl.
2. The compound of claim 1, wherein L is ##STR00015##
3. The compound of claim 2, wherein L is ##STR00016##
4. The compound of claim 3, wherein X is --CH.sub.2--, p1 is 1, p2
is 1 or 2, q1 is 1, r2 is 1 or 2, each of m1 and m2 is
independently 0 or 1, and each of R' and R'' is independently
hydrogen or alkyl.
5. The compound of claim 4, wherein L is ##STR00017##
6. The compound of claim 2, wherein L is ##STR00018##
7. The compound of claim 6, wherein X is --CH.sub.2--, p1 is 0 or
1, p2 is 1 or 2, q1 is 1, q2 is 1 or 2, each of m1 and m2 is
independently 0 or 1, and each of R' and R'' is independently
hydrogen or alkyl.
8. The compound of claim 7, wherein L is ##STR00019##
9. The compound of claim 2, wherein X.sup.1 is a bond or C.sub.1-4
alkylene that is optionally linked terminally to --N(R.sup.2)--,
where R.sup.2 is hydrogen or alkyl.
10. The compound of claim 2, wherein X.sup.2 is a bond or C.sub.1-4
alkylene.
11. The compound of claim 2, wherein Y is --N(R''')--, --O--,
--S--, or a bond where R''' is hydrogen, alkyl, cycloalkyl,
cycloalkylalkyl, aryl, aralkyl, heterocyclyl, or
heterocyclylalkyl.
12. The compound of claim 11, wherein R''' is hydrogen,
cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, aralkyl,
or heteroaralkyl.
13. The compound of claim 2, wherein each of R.sup.2 and R.sup.3 is
independently hydrogen or alkyl.
14. The compound of claim 2, wherein R.sup.1 is hydrogen, alkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, or
heterocyclylalkyl.
15. The compound of claim 2, wherein R.sup.1 is hydrogen, or
R.sup.1 is phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,
imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,
triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl,
pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, indolyl,
isoindolyl, benzofuryl, benzothiophenyl, benzimidazolyl,
benzthiazolyl, furopyridyl, or thienopyridyl; each of which being
optionally substituted with C.sub.1-4 alkyl, halo, hydroxy,
C.sub.1-4 alkoxy, or C.sub.1-4 alkylthio.
16. The compound of claim 2, wherein A is heteroaryl.
17. The compound of claim 3, wherein X.sup.1 is a bond or C.sub.1-4
alkylene that is optionally linked terminally to --N(R.sup.2)--;
X.sup.2 is a bond or C.sub.1-4 alkylene; Y is --N(R''')--, --O--,
--S--, or a bond where R''' is hydrogen, cycloalkylalkyl,
heterocycloalkylalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;
each of R.sup.2 and R.sup.3 is independently hydrogen or alkyl;
R.sup.1 is cycloalkyl, cycloalkylalkyl, aryl, aralkyl,
heterocyclyl, or heterocyclylalkyl; and A is heteroaryl.
18. The compound of claim 17, wherein X.sup.1 is a bond; each of
R.sup.2 and R.sup.3 is hydrogen; and R.sup.1 is aryl or
heteroaryl.
19. The compound of claim 17, wherein X is --CH.sub.2--, p1 is 1,
p2 is 1 or 2, q1 is 1, r2 is 1 or 2, each of m1 and m2 is
independently 0 or 1, and each of R' and R'' is independently
hydrogen or alkyl.
20. The compound of claim 6, wherein X.sup.1 is a bond or C.sub.1-4
alkylene that is optionally linked terminally to --N(R.sup.2)--
where R.sup.2 is hydrogen or alkyl; X.sup.2 is a bond or C.sub.1-4
alkylene; Y is --N(R''')--, --O--, --S--, or a bond where R''' is
hydrogen, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl,
aralkyl, or heteroaralkyl; each of R.sup.2 and R.sup.3 is
independently hydrogen or alkyl; R.sup.1 is cycloalkyl,
cycloalkylalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl;
and A is heteroaryl.
21. The compound of claim 20, wherein X is --CH.sub.2--, p1 is 0 or
1, p2 is 1 or 2, q1 is 1, q2 is 1 or 2, each of m1 and m2 is
independently 0 or 1, and each of R' and R'' is independently
hydrogen or alkyl.
22. The compound of claim 1, said compound being selected from the
group consisting of: (7RS,
9aRS)-[2-(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)-
-octahydro-pyrido[1,2-a]pyrazin-7-yl]-methanol; (6RS,
9aRS)-[2-(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)-
-octahydro-pyrido[1,2-a]pyrazin-6-yl]-methanol; (7RS,
9aRS)-[2-(5-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-octa-
hydro-pyrido[1,2-a]pyrazin-7-yl]-methanol; (7RS,
9aRS)-[2-(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-octa-
hydro-pyrido[1,2-a]pyrazin-7-yl]-methanol; (7RS,
9aSR)-5-[7-(3-fluoro-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]--
2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (7RS,
9aRS)-2-furan-2-yl-N.sup.5-(2-pyrimidin-2-yl-octahydro-pyrido[1,2-a]pyraz-
in-7-ylmethyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine;
(7RS,
9aSR)--N.sup.5-[2-(5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmet-
hyl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl]-2-furan-2-yl-[1,2,4]triazo-
lo[1,5-a][1,3,5]triazine-5,7-diamine; (7RS,
9aSR)-2-furan-2-yl-N.sup.5-(2-pyrimidin-2-yl-octahydro-pyrido[1,2-a]pyraz-
in-7-ylmethyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine;
(7RS,
9aRS)-5-(7-aminomethyl-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-yl--
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (7RS,
9aRS)-5-{7-[(bis-pyridin-4-ylmethyl-amino)-methyl]-octahydro-pyrido[1,2-a-
]pyrazin-2-yl}-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine-
; (7RS,
9aRS)-2-furan-2-yl-5-[7-(pyrimidin-2-ylaminomethyl)-octahydro-pyri-
do[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,
9aRS)-2-furan-2-yl-5-(7-{[(pyridin-4-ylmethyl)-amino]-methyl}-octah-
ydro-pyrido[1,2-a]pyrazin-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yla-
mine;
2-furan-2-yl-5-[5-(5-methyl-isoxazol-3-ylmethyl)-2,5-diaza-bicyclo[2-
.2.1]hept-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
5-[5-(4-fluoro-benzyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-2-furan-2-yl-[1-
,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
5-[5-(4-chloro-benzyl)-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl]-2-furan-2-yl--
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
5-[1-(2,6-dichloro-benzyl)-hexahydro-pyrrolo[3,4-b]pyrrol-5-yl]-2-furan-2-
-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(.+-.)-2-furan-2-yl-5-(octahydro-pyrido[1,2-a]pyrazin-2-yl)-[1,2,4]triazo-
lo[1,5-a][1,3,5]triazin-7-ylamine;
(.+-.)-2-furan-2-yl-5-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-[1,2,4]triaz-
olo[1,5-a][1,3,5]triazin-7-ylamine;
(S)-2-furan-2-yl-5-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-[1,2,4]triazolo-
[1,5-a][1,3,5]triazin-7-ylamine;
(3S,8aS)-5-(3-benzyl-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-2-furan-2-yl-[-
1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (7RS,
9aSR)-[2-(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)-
-octahydro-pyrido[1,2-a]pyrazin-7-yl]-methanol; (7RS,
9aRS)-5-[7-(2,4-difluoro-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazin-2--
yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,
9aRS)-2-furan-2-yl-5-[7-(quinolin-6-yloxymethyl)-octahydro-pyrido[1,2-a]p-
yrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (7RS,
9aRS)-2-furan-2-yl-5-(7-phenoxymethyl-octahydro-pyrido[1,2-a]pyrazin-2-yl-
)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (7RS,
9aRS)-2-furan-2-yl-5-[7-(5,6,7,8-tetrahydro-naphthalen-2-yloxymethyl)-oct-
ahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-y-
lamine; (7RS,
9aRS)-5-[7-(2-fluoro-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]--
2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (7RS,
9aRS)-5-[7-(3-fluoro-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]--
2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (7RS,
9aRS)-5-[7-(4-fluoro-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]--
2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (7RS,
9aRS)-2-furan-2-yl-5-[7-(4-methoxy-phenoxymethyl)-octahydro-pyrido[1,2-a]-
pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (7RS,
9aRS)-2-furan-2-yl-5-[7-(2,3,5-trifluoro-phenoxymethyl)-octahydro-pyrido[-
1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,
9aRS)-2-furan-2-yl-5-[7-(2,4,6-trifluoro-phenoxymethyl)-octahydro-pyrido[-
1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,
9aRS)-2-furan-2-yl-5-[7-(pyridin-2-yloxymethyl)-octahydro-pyrido[1,2-a]py-
razin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (7RS,
9aRS)-2-furan-2-yl-5-[7-(pyridin-3-yloxymethyl)-octahydro-pyrido[1,2-a]py-
razin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (7RS,
9aRS)-2-furan-2-yl-5-[7-(pyridin-4-yloxymethyl)-octahydro-pyrido[1,2-a]py-
razin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (7RS,
9aRS)-2-furan-2-yl-5-[7-(4-trifluoromethyl-pyrimidin-2-yloxymethyl)-octah-
ydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yla-
mine; (7RS,
9aRS)-2-furan-2-yl-5-[7-(6-trifluoromethyl-pyrimidin-4-yloxymethyl)-octah-
ydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yla-
mine; (7RS,
9aRS)-2-furan-2-yl-5-[7-(quinazolin-2-yloxymethyl)-octahydro-pyrido[1,2-a-
]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,
9aRS)-2-furan-2-yl-5-[7-(isoquinolin-3-yloxymethyl)-octahydro-pyrido[1,2--
a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,
9aRS)-2-furan-2-yl-5-[7-(isoquinolin-5-yloxymethyl)-octahydro-pyrido[1,2--
a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,
9aRS)-2-furan-2-yl-5-[7-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxymethyl)-octah-
ydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yla-
mine; (7RS,
9aRS)-2-furan-2-yl-5-(7-imidazol-1-ylmethyl-octahydro-pyrido[1,2-a]pyrazi-
n-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (7RS,
9aRS)-2-furan-2-yl-5-(7-[1,2,4]triazol-1-ylmethyl-octahydro-pyrido[1,2-a]-
pyrazin-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (7RS,
9aRS)-2-furan-2-yl-5-(7-tetrazol-1-ylmethyl-octahydro-pyrido[1,2-a]pyrazi-
n-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (7RS,
9aSR)-5-[7-(2,4-difluoro-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazin-2--
yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,
9aSR)-2-furan-2-yl-5-[7-(4-methoxy-phenoxymethyl)-octahydro-pyrido[1,2-a]-
pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (7RS,
9aSR)-2-furan-2-yl-5-(7-phenoxymethyl-octahydro-pyrido[1,2-a]pyrazin-2-yl-
)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (7RS,
9aSR)-2-furan-2-yl-5-[7-(5,6,7,8-tetrahydro-naphthalen-2-yloxymethyl)-oct-
ahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-y-
lamine; (7RS,
9aSR)-2-furan-2-yl-5-[7-(pyridin-2-yloxymethyl)-octahydro-pyrido[1,2-a]py-
razin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (7RS,
9aSR)-2-furan-2-yl-5-[7-(pyridin-3-yloxymethyl)-octahydro-pyrido[1,2-a]py-
razin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (7RS,
9aSR)-2-furan-2-yl-5-[7-(pyridin-4-yloxymethyl)-octahydro-pyrido[1,2-a]py-
razin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (7RS,
9aSR)-5-[7-(benzo[1,3]dioxol-5-yloxymethyl)-octahydro-pyrido[1,2-a]pyrazi-
n-2-yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,
9aSR)-2-furan-2-yl-5-[7-(quinazolin-2-yloxymethyl)-octahydro-pyrido[1,2-a-
]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,
9aSR)-2-furan-2-yl-5-[7-(quinolin-2-yloxymethyl)-octahydro-pyrido[1,2-a]p-
yrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (7RS,
9aSR)-2-furan-2-yl-5-[7-(isoquinolin-3-yloxymethyl)-octahydro-pyrido[1,2--
a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,
9aSR)-2-furan-2-yl-5-[7-(isoquinolin-5-yloxymethyl)-octahydro-pyrido[1,2--
a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,
9aSR)-5-[7-(2-fluoro-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]--
2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (7RS,
9aSR)-5-[7-(4-fluoro-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]--
2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (6RS,
9aRS)-[2-furan-2-yl-5-(6-phenoxymethyl-octahydro-pyrido[1,2-a]pyrazin-2-y-
l)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (6RS,
9aRS)-[2-furan-2-yl-5-[6-(5,6,7,8-tetrahydro-naphthalen-1-yloxymethyl)-oc-
tahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7--
ylamine; (6RS,
9aRS)-[5-[6-(3-amino-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]--
2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (6RS,
9aRS)-[5-[6-(benzo[1,3]dioxol-5-yloxymethyl)-octahydro-pyrido[1,2-a]pyraz-
in-2-yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(6RS,
9aRS)-[2-furan-2-yl-5-[6-(1H-indol-5-yloxymethyl)-octahydro-pyrido[-
1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(6RS,
9aRS)-[1-[2-(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5--
yl)-octahydro-pyrido[1,2-a]pyrazin-6-ylmethyl]-1H-indol-5-ol; (7RS,
9aRS)-3-amino-5-{7-[(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]tr-
iazin-5-ylamino)-methyl]-octahydro-pyrido[1,2-a]pyrazin-2-yl}-6-chloro-pyr-
azine-2-carboxylic acid methyl ester; (7RS,
9aRS)--N-5-[2-(3,5-difluoro-phenyl)-octahydro-pyrido[1,2-a]pyrazin-7-ylme-
thyl]-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine;
(7RS,
9aRS)--N-5-[2-(2,4-difluoro-benzyl)-octahydro-pyrido[1,2-a]pyrazin--
7-ylmethyl]-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine-
; (7RS,
9aSR)-5-(7-aminomethyl-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-fura-
n-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (7RS,
9aRS)-5-(7-{[bis-(2-fluoro-benzyl)-amino]-methyl}-octahydro-pyrido[1,2-a]-
pyrazin-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,
9aRS)-5-(7-{[bis-(2,4-difluoro-benzyl)-amino]-methyl}-octahydro-pyr-
ido[1,2-a]pyrazin-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin--
7-ylamine; (7RS,
9aRS)-5-{7-[(2,4-difluoro-benzylamino)-methyl]-octahydro-pyrido[1,2-a]pyr-
azin-2-yl}-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,
9aRS)-5-(7-{[bis-(2,4,6-trifluoro-benzyl)-amino]-methyl}-octahydro--
pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triaz-
in-7-ylamine; (7RS,
9aRS)-5-(7-{[bis-(2,3-difluoro-benzyl)-amino]-methyl}-octahydro-pyrido[1,-
2-a]pyrazin-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylam-
ine; (7RS,
9aRS)-5-(7-{[bis-(2,6-difluoro-benzyl)-amino]-methyl}-octahydro-
-pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]tria-
zin-7-ylamine; (7RS,
9aRS)-5-(7-{[bis-(3,5-difluoro-benzyl)-amino]-methyl}-octahydro-pyrido[1,-
2-a]pyrazin-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylam-
ine; (7RS,
9aRS)-5-(7-{[bis-(5-chloro-furan-2-ylmethyl)-amino]-methyl}-oct-
ahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,-
5]triazin-7-ylamine; (7RS,
9aRS)-5-{7-[(bis-pyridin-2-ylmethyl-amino)-methyl]-octahydro-pyrido[1,2-a-
]pyrazin-2-yl}-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine-
; (7RS,
9aRS)-5-{7-[(bis-pyridin-3-ylmethyl-amino)-methyl]-octahydro-pyrid-
o[1,2-a]pyrazin-2-yl}-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7--
ylamine; (7RS,
9aRS)-2-furan-2-yl-5-(7-{[(pyridin-3-ylmethyl)-amino]-methyl}-octahydro-p-
yrido[1,2-a]pyrazin-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,
9aRS)-5-(7-{[bis-(2-chloro-1-methyl-4-trifluoromethyl-1H-pyrrol-3-y-
lmethyl)-amino]-methyl}-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-yl--
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; (7RS,
9aRS)-5-(7-{[bis-(3,5-dimethyl-isoxazol-4-ylmethyl)-amino]-methyl}-octahy-
dro-pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]t-
riazin-7-ylamine; (7RS,
9aRS)-5-(7-{[(3,5-dimethyl-isoxazol-4-ylmethyl)-amino]-methyl}-octahydro--
pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triaz-
in-7-ylamine; (7RS,
9aRS)-5-{7-[(bis-cyclohexylmethyl-amino)-methyl]-octahydro-pyrido[1,2-a]p-
yrazin-2-yl}-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,
9aRS)-5-{7-[(bis-furan-2-ylmethyl-amino)-methyl]-octahydro-pyrido[1-
,2-a]pyrazin-2-yl}-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yla-
mine; (7RS,
9aRS)-5-(7-{[bis-(1H-pyrrol-2-ylmethyl)-amino]-methyl}-octahydro-pyrido[1-
,2-a]pyrazin-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yla-
mine; (7RS,
9aRS)-5-(7-{[bis-(5-chloro-1,3-dimethyl-1H-pyrazol-4-ylmethyl)-amino]-met-
hyl}-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-
-a][1,3,5]triazin-7-ylamine; (7RS,
9aRS)-5-(7-{[(5-chloro-1,3-dimethyl-1H-pyrazol-4-ylmethyl)-amino]-methyl}-
-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a][-
1,3,5]triazin-7-ylamine; (7RS,
9aRS)-5-{7-[(bis-thiazol-2-ylmethyl-amino)-methyl]-octahydro-pyrido[1,2-a-
]pyrazin-2-yl}-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine-
; (7RS,
9aRS)-5-{7-[(bis-thiophen-2-ylmethyl-amino)-methyl]-octahydro-pyri-
do[1,2-a]pyrazin-2-yl}-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-
-ylamine; (7RS,
9aRS)-5-(7-{[bis-(5-methyl-thiophen-2-ylmethyl)-amino]-methyl}-octahydro--
pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triaz-
in-7-ylamine; (7RS,
9aSR)-2-furan-2-yl-5-[7-(pyrimidin-2-ylaminomethyl)-octahydro-pyrido[1,2--
a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,
9aSR)-5-{7-[(bis-pyridin-4-ylmethyl-amino)-methyl]-octahydro-pyrido[1,2-a-
]pyrazin-2-yl}-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine-
; (7RS,
9aSR)-2-furan-2-yl-5-(7-{[(pyridin-4-ylmethyl)-amino]-methyl}-octa-
hydro-pyrido[1,2-a]pyrazin-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yl-
amine; (7RS,
9aSR)-5-{7-[(bis-pyridin-3-ylmethyl-amino)-methyl]-octahydro-pyrido[1,2-a-
]pyrazin-2-yl}-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine-
; (7RS,
9aSR)-2-furan-2-yl-5-(7-{[(pyridin-3-ylmethyl)-amino]-methyl}-octa-
hydro-pyrido[1,2-a]pyrazin-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yl-
amine; (7RS,
9aSR)-5-{7-[(bis-furan-2-ylmethyl-amino)-methyl]-octahydro-pyrido[1,2-a]p-
yrazin-2-yl}-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,
9aSR)-2-furan-2-yl-5-(7-{[(furan-2-ylmethyl)-amino]-methyl}-octahyd-
ro-pyrido[1,2-a]pyrazin-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylami-
ne; (7RS,
9aSR)-5-(7-{[bis-(3,5-dimethyl-isoxazol-4-ylmethyl)-amino]-methy-
l}-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a-
][1,3,5]triazin-7-ylamine; (7RS,
9aSR)-5-(7-{[(3,5-dimethyl-isoxazol-4-ylmethyl)-amino]-methyl}-octahydro--
pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triaz-
in-7-ylamine;
(R)-2-furan-2-yl-5-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-[1,2,4]triazolo-
[1,5-a][1,3,5]triazin-7-ylamine;
2-furan-2-yl-5-(1-quinolin-2-ylmethyl-hexahydro-pyrrolo[3,4-b]pyrrol-5-yl-
)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine; and (7RS,
9aRS)-2-furan-2-yl-5-[7-(quinolin-7-yloxymethyl)-octahydro-pyrido[1,2-a]p-
yrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine.
23. The compound of claim 1, said compound being selected from the
group consisting of:
(.+-.)2-furan-2-yl-5-(octahydro-pyrido[1,2-a]pyrazin-2-yl)-[1,2,4]triazol-
o[1,5-a][1,3,5]triazin-7-ylamine;
(.+-.)2-furan-2-yl-5-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-[1,2,4]triazo-
lo[1,5-a][1,3,5]triazin-7-ylamine; (7RS,
9aRS)-[2-(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)-
-octahydro-pyrido[1,2-a]pyrazin-7-yl]-methanol; (6RS,
9aRS)-[2-(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)-
-octahydro-pyrido[1,2-a]pyrazin-6-yl]-methanol;
(7RS,9aRS)-2-Furan-2-yl-5-[7-(quinolin-6-yloxymethyl)-octahydro-pyrido[1,-
2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,9aRS)-2-Furan-2-yl-5-(7-phenoxymethyl-octahydro-pyrido[1,2-a]pyrazin-
-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,9aRS)-5-[7-(2-fluoro-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazin-2-
-yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,9aRS)-5-[7-(3-fluoro-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazin-2-
-yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,9aRS)-2-furan-2-yl-5-[7-(pyridin-3-yloxymethyl)-octahydro-pyrido[1,2-
-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,9aRS)-2-furan-2-yl-5-[7-(isoquinolin-5-yloxymethyl)-octahydro-pyrido-
[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,9aRS)-2-furan-2-yl-5-[7-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxymethyl)--
octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin--
7-ylamine;
(7RS,9aRS)-2-furan-2-yl-5-(7-imidazol-1-ylmethyl-octahydro-pyri-
do[1,2-a]pyrazin-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,9aRS)-2-furan-2-yl-5-(7-[1,2,4]triazol-1-ylmethyl-octahydro-pyrido[1-
,2-a]pyrazin-2-yl)]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,9aSR)-2-furan-2-yl-5-[7-(quinolin-2-yloxymethyl)-octahydro-pyrido[1,-
2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(6RS,9aRS)-2-furan-2-yl-5-(6-phenoxymethyl-octahydro-pyrido[1,2-a]pyrazin-
-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,9aRS)-2-furan-2-yl-N-5-(2-pyrimidin-2-yl-octahydro-pyrido[1,2-a]pyra-
zin-7-ylmethyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine;
(7RS,9aRS)-5-(7-aminomethyl-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan--
2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,9aSR)-5-(7-aminomethyl-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan--
2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,9aRS)-5-{7-[(2,4-difluoro-benzylamino)-methyl]-octahydro-pyrido[1,2--
a]pyrazin-2-yl}-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamin-
e;
(7RS,9aRS)-5-{7-[(bis-pyridin-4-ylmethyl-amino)-methyl]-octahydro-pyrid-
o[1,2-a]pyrazin-2-yl}-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7--
ylamine;
(7RS,9aRS)-2-furan-2-yl-5-(7-{[(pyridin-4-ylmethyl)-amino]-methyl-
}-octahydro-pyrido[1,2-a]pyrazin-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazi-
n-7-ylamine;
(7RS,9aRS)-5-{7-[(bis-pyridin-2-ylmethyl-amino)-methyl]-octahydro-pyrido[-
1,2-a]pyrazin-2-yl}-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yl-
amine;
(7RS,9aRS)-5-{7-[(bis-pyridin-3-ylmethyl-amino)-methyl]-octahydro-p-
yrido[1,2-a]pyrazin-2-yl}-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazi-
n-7-ylamine;
(7RS,9aRS)-2-furan-2-yl-5-[7-(pyrimidin-2-ylaminomethyl)-octahydro-pyrido-
[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,9aRS)-5-(7-{[(5-chloro-1,3-dimethyl-1H-pyrazol-4-ylmethyl)-amino]-me-
thyl}-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,-
5-a][1,3,5]triazin-7-ylamine;
(7RS,9aSR)-5-{7-[(bis-pyridin-3-ylmethyl-amino)-methyl]-octahydro-pyrido[-
1,2-a]pyrazin-2-yl}-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yl-
amine;
(R)-2-furan-2-yl-5-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-[1,2,4]tr-
iazolo[1,5-a][1,3,5]triazin-7-ylamine; and (7RS,
9aRS)-2-furan-2-yl-5-[7-(quinolin-7-yloxymethyl)-octahydro-pyrido[1,2-a]p-
yrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine.
24. The compound of claim 1, said compound being selected from the
group consisting of:
(7RS,9aRS)-2-furan-2-yl-5-[7-(quinolin-6-yloxymethyl)-octahydro-pyrido[1,-
2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,9aRS)-5-[7-(3-fluoro-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazin-2-
-yl]-2-furan-2-yl-]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine;
(7RS,9aRS)-2-furan-2-yl-N-5-(2-pyrimidin-2-yl-octahydro-pyrido[1,2-a]pyra-
zin-7-ylmethyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine;
(7RS,9aRS)-5-{7-[(bis-pyridin-3-ylmethyl-amino)-methyl]-octahydro-pyrido[-
1,2-a]pyrazin-2-yl}-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yl-
amine; and (7RS,
9aRS)-2-furan-2-yl-5-[7-(quinolin-7-yloxymethyl)-octahydro-pyrido[1,2-a]p-
yrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine.
25. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable carrier.
26. A pharmaceutical composition comprising a compound of claim 22
and a pharmaceutically acceptable carrier.
27. A method of treating Parkinson's disease in a subject, the
method comprising the step of administering to said subject an
effective amount of a compound of claim 1.
Description
BACKGROUND OF THE INVENTION
Adenosine is a ubiquitous biochemical messenger. Adenosine binds to
and activates certain seven transmembrane-spanning G-protein
coupled receptors, eliciting a variety of physiological responses.
Adenosine receptors are divided into four known subtypes (i.e.
A.sub.1, A.sub.2a, A.sub.2b, and A.sub.3). These receptor subtypes
mediate different and sometimes opposing effects. In general,
activation of the adenosine A.sub.2a or A.sub.2b receptor leads to
an increase in cellular cAMP levels, while activation of the
adenosine A.sub.1 or A.sub.3 receptor leads to a decrease in
cellular cAMP levels. A.sub.2a adenosine receptors are abundant in
the basal ganglia, a region of the brain associated with the
pathphysiology of Parkinson's disease. For reviews concerning
A.sub.2a adenosine receptors, see, e.g., Moreau et al., Brain
Research Reviews 31:65-82 (1999) and Svenningsson et al., Progress
in Neurobiology 59:355-396 (1999). For a discussion of the role and
regulation of adenosine in the central nervous system, see, e.g.,
Dunwiddie et al., Ann. Rev. Neuroscience 24:31-55 (2001).
SUMMARY OF THE INVENTION
The invention is based on the discovery that compounds of formula
(I) are unexpectedly potent antagonists of the A.sub.2a subtype of
adenosine receptors. Many compounds of formula (I) also selectively
inhibit the A.sub.2a adenosine receptors. Adenosine antagonists of
the present invention are useful in the prevention and/or treatment
of various diseases and disorders related to modulation of A.sub.2a
adenosine receptor signaling pathways. Such a disease or disorder
can be, e.g., neurodegenerative diseases such as Parkinson's
disease and Parkinson's-like syndromes such as progressive
supranuclear palsy and multiple system atrophy, senile dementia
such as Alzheimer's disease, depression, AIDS encephalopathy,
multiple sclerosis, amyotrophic lateral sclerosis, migraine,
attention deficit disorder, narcolepsy, sleep apnea or other
disorders that cause excessive daytime sleepiness, Huntington's
disease, cerebral ischemia, brain trauma, hepatic fibrosis,
cirrhosis, and fatty liver.
In one aspect, the invention features compounds of formula (I):
##STR00002##
A can be an aryl or heteroaryl. Each of B, B.sup.1, and B.sup.2,
independently, can be N or CR.sup.2; provided that at least one of
B.sup.1 and B.sup.2 is N. Each of R.sup.2 and R.sup.3,
independently, can be hydrogen, alkyl, cycloalkyl, cycloalkenyl,
aryl, aralkyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, or
heteroaralkyl. X.sup.1 can be a bond or C.sub.1-6 alkylene,
C.sub.2-6 alkenylene, or C.sub.2-6 alkynylene, and each of the
C.sub.1-6 alkylene, C.sub.2-6 alkenylene, and C.sub.2-6 alkynylene
can be optionally interrupted by or linked terminally to --O--,
--S--, or --N(R.sup.2)--. For example, X.sup.1 can be a propylene
that is interrupted by --O-- (e.g.,
--CH.sub.2--CH.sub.2--O--CH.sub.2--) or X.sup.1 can be an ethylene
that is linked terminally to --NH-- (e.g.,
--CH.sub.2--CH.sub.2--NH-- or --NH--CH.sub.2--CH.sub.2--). X.sup.2
is a bond, C.sub.1-6 alkylene, C.sub.2-6 alkenylene, or C.sub.2-6
alkynylene. Y is --C(R.sup.2)(R.sup.3)--, --N(R''')--, --O--,
--S--, --SO--, --SO.sub.2--, --CO--, --CO.sub.2--, or a bond where
R''' is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl,
heterocyclyl, or heterocyclylalkyl. R.sup.1 is hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,
cycloalkenylalkyl, aryl, aralkyl, heterocyclyl, or
heterocyclylalkyl. L is a linker selected from the group consisting
of:
##STR00003## wherein each of R' and R'', independently, can be
hydrogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy,
amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy,
sulfo, sulfoxy, mercapto, alkylsulfanyl, alkylsulfinyl,
alkylsulfonyl, aminocarbonyl, alkylcarbonylamino,
alkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea,
thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl,
cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl,
heterocycloalkyloxy, heterocycloalkylsulfanyl, aryl, aryloxy,
arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl,
or heteroaroyl; X is --C(R.sup.2)(R.sup.3)--, --N(R.sup.2)--,
--O--, or --S-- (where each of R.sup.2 and R.sup.3 has been defined
above); each of p1, p2, q1, q2, m1, and m2, independently, can be
0-2; each of r and r1 is independently is 1-2; and r2 is 0-1.
##STR00004## In one embodiment, X is --CH.sub.2--, p1 is 1, p2 is 1
or 2, q1 is 1, r2 is 1 or 2, each of m1 and m2 is independently 0
or 1, and each of R' and R'' is independently hydrogen or alkyl.
For example, L can be
##STR00005## In one embodiment, X is --CH.sub.2--, p1 is 0 or 1, p2
is 1 or 2, q1 is 1, q2 is 1 or 2, each of m1 and m2 is
independently 0 or 1, and each of R' and R'' is independently
hydrogen or alkyl. For example, L can be
##STR00006##
In one embodiment, X.sup.1 can be a bond or C.sub.1-4 alkylene that
is optionally linked terminally to --N(R.sup.2)--, where R.sup.2 is
hydrogen or alkyl.
In one embodiment, X.sup.2 can be a bond or C.sub.1-4 alkylene.
In one embodiment, Y can be --N(R''')--, --O--, --S--, or a bond
where R''' can be hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,
aryl, aralkyl, heterocyclyl, or heterocyclylalkyl. For example,
R''' can be hydrogen, cycloalkylalkyl, heterocycloalkylalkyl, aryl,
heteroaryl, aralkyl, or heteroaralkyl.
In one embodiment, B can be N.
In one embodiment, each of B.sup.1 and B.sup.2, independently, can
be N or CH.
In one embodiment, each of R.sup.2 and R.sup.3, independently, can
be hydrogen or alkyl.
In one embodiment, R.sup.1 is hydrogen, alkyl, cycloalkyl,
cycloalkylalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl.
For example, R.sup.1 can be hydrogen, or R.sup.1 can be phenyl,
furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,
thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
triazinyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl,
benzofuryl, benzothiophenyl, benzimidazolyl, benzthiazolyl,
furopyridyl, or thienopyridyl; each of these cyclic moieties can be
optionally substituted with C.sub.1-4 alkyl, halo, hydroxy,
C.sub.1-4 alkoxy, or C.sub.1-4 alkylthio.
In one embodiment, A can be heteroaryl.
In one embodiment, L is
##STR00007## (where X can be --CH.sub.2--, p1 can be 1, p2 can be 1
or 2, q1 can be 1, r2 can be 1 or 2, each of m1 and m2,
independently, can be 0 or 1, and each of R' and R'',
independently, can be hydrogen or alkyl); X.sup.1 is a bond or
C.sub.1-4 alkylene that is optionally linked terminally to
--N(R.sup.2)--; X.sup.2 is a bond or C.sub.1-4 alkylene; Y is
--N(R''')--, --O--, --S--, or a bond where R''' is hydrogen,
cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl, aralkyl,
or heteroaralkyl; B is N; each of B.sup.1 and B.sup.2,
independently, is N or CH; each of R.sup.2 and R.sup.3 is
independently hydrogen or alkyl; R.sup.1 is cycloalkyl,
cycloalkylalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl;
and A is heteroaryl. For example, X.sup.1 can be a bond; each of
R.sup.2 and R.sup.3 can be hydrogen; and R.sup.1 can be aryl or
heteroaryl.
In one embodiment, L is
##STR00008## (where X can be --CH.sub.2--, p1 can be 0 or 1, p2 can
be 1 or 2, q1 can be 1, q2 can be 1 or 2, each of m1 and m2,
independently, can be 0 or 1, and each of R' and R'' can be
independently hydrogen or alkyl); X.sup.1 is a bond or C.sub.1-4
alkylene that is optionally linked terminally to --N(R.sup.2)--
where R.sup.2 is hydrogen or alkyl; X.sup.2 is a bond or C.sub.1-4
alkylene; Y is --N(R''')--, --O--, --S--, or a bond where R''' is
hydrogen, cycloalkylalkyl, heterocycloalkylalkyl, aryl, heteroaryl,
aralkyl, or heteroaralkyl; B is N; each of B.sup.1 and B.sup.2,
independently, is N or CH; each of R.sup.2 and R.sup.3 is
independently hydrogen or alkyl; R.sup.1 is cycloalkyl,
cycloalkylalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl;
and A is heteroaryl.
Some examples of a compound of formula (I) are shown in Examples
1-153 below.
An N-oxide derivative or a pharmaceutically acceptable salt of each
of the compounds of formula (I) is also within the scope of this
invention. For example, a nitrogen ring atom of the
triazolotriazine or the pyrazolotriazine core ring or a
nitrogen-containing heterocyclyl substituent can form an oxide in
the presence of a suitable oxidizing agent such as
m-chloroperbenzoic acid or H.sub.2O.sub.2.
A compound of formula (I) that is acidic in nature (e.g., having a
carboxyl or phenolic hydroxyl group) can form a pharmaceutically
acceptable salt such as a sodium, potassium, calcium, or gold salt.
Also within the scope of the invention are salts formed with
pharmaceutically acceptable amines such as ammonia, alkyl amines,
hydroxyalkylamines, and N-methylglycamine. A compound of formula
(I) can be treated with an acid to form acid addition salts.
Examples of such an acid include hydrochloric acid, hydrobromic
acid, hydroiodic acid, sulfuric acid, methanesulfonic acid,
phosphoric acid, p-bromophenyl-sulfonic acid, carbonic acid,
succinic acid, citric acid, benzoic acid, oxalic acid, malonic
acid, salicylic acid, malic acid, fumaric acid, ascorbic acid,
maleic acid, acetic acid, and other mineral and organic acids well
known to a skilled person in the art. The acid addition salts can
be prepared by treating a compound of formula (I) in its free base
form with a sufficient amount of an acid (e.g., hydrochloric acid)
to produce an acid addition salt (e.g., a hydrochloride salt). The
acid addition salt can be converted back to its free base form by
treating the salt with a suitable dilute aqueous basic solution
(e.g., sodium hydroxide, sodium bicarbonate, potassium carbonate,
or ammonia). Compounds of formula (I) can also be, e.g., in a form
of achiral compounds, racemic mixtures, optically active compounds,
pure diastereomers, or a mixture of diastereomers.
Compounds of formula (I) exhibit surprisingly high affinity to the
A.sub.2a subtype of adenosine receptors, e.g., with K.sub.i values
of less than 10 .mu.M under conditions as described in Example 154.
Some compounds of formula (I) exhibit K.sub.i values of below 1
.mu.M. Many compounds of formula (I) are selectively inhibitors of
the A.sub.2a adenosine receptors (e.g., these compounds inhibit the
A.sub.2a adenosine receptors at least 10 times better than other
subtypes of adenosine receptors, e.g., the A.sub.1 adenosine
receptors or the A.sub.3 adenosine receptors.
Compounds of formula (I) can also be modified by appending
appropriate functionalities to enhance selective biological
properties. Such modifications are known in the art and include
those that increase biological penetration into a given biological
system (e.g., blood, lymphatic system, central nervous system),
increase oral availability, increase solubility to allow
administration by injection, alter metabolism, and/or alter rate of
excretion. Examples of these modifications include, but are not
limited to, esterification with polyethylene glycols,
derivatization with pivolates or fatty acid substituents,
conversion to carbamates, hydroxylation of aromatic rings, and
heteroatom-substitution in aromatic rings.
In another aspect, the present invention features a pharmaceutical
composition comprising a compound of formula (I) (or a combination
of two or more compounds of formula (I)) and a pharmaceutically
acceptable carrier. Also included in the present invention is a
medicament composition including any of the compounds of formula
(I), alone or in a combination, together with a suitable
excipient.
In a further aspect, the invention features a method of inhibiting
the A.sub.2a adenosine receptors (e.g., with an K.sub.i value of
less than 10 .mu.M; preferably, less than 1 .mu.M) in a cell,
including the step of contacting the cell with an effective amount
of one or more compounds of formula (I). Also with the scope of the
invention is a method of modulating the A.sub.2a adenosine receptor
signaling pathways in a cell or in a subject (e.g., a mammal such
as human), including the step of contacting the cell with or
administering to the subject an effective amount of one or more of
a compound of formula (I).
Also within the scope of the present invention is a method of
treating a subject or preventing a subject suffering from a
condition or a disease wherein the causes or symptoms of the
condition or disease are associated with an activation of the
A.sub.2a adenosine receptor. The method includes the step of
administering to the subject an effective amount of one or more of
a compound of formula (I). The conditions or diseases can be, e.g.,
neurodegenerative diseases such as Parkinson's disease and
Parkinson's-like syndromes such as progressive supranuclear palsy
and multiple system atrophy, senile dementia such as Alzheimer's
disease, depression, AIDS encephalopathy, multiple sclerosis,
amyotrophic lateral sclerosis, migraine, attention deficit
disorder, narcolepsy, sleep apnea or other disorders that cause
excessive daytime sleepiness, Huntington's disease, cerebral
ischemia, brain trauma, hepatic fibrosis, cirrhosis, and fatty
liver.
Compounds of formula (I) may be utilized as sedatives, muscle
relaxants, antipsychotics, antidepressants, anxiolytics,
analgesics, respiratory stimulants, antiepileptics,
anticonvulsants, and cardioprotective agents.
Also within the scope of the invention is a method of treating or
preventing a condition or a disease characterized by or resulted
from an over-activation of the A.sub.2a adenosine receptor by
administering to a subject in need of such a treatment an effective
amount of any of compounds of formula (I) in combination with one
or more known A.sub.2a antagonists. For example, a patient
suffering from Parkinson's disease can be treated by administering
an effective amount of a compound of formula (I) in combination
with an agent such as L-DOPA, a dopaminergic agonist, an inhibitor
of monoamine oxidase (type B), a DOPA decarboxylase inhibitor, or a
catechol-O-methyltransferase inhibitor. The compound of formula (I)
and the agent can be administered to a patient simultaneously or in
sequence. The invention also includes a pharmaceutical composition
containing one or more of a compound of formula (I), one or more of
a known A.sub.2a antagoinst, and a suitable excipient.
As used herein, an "alkyl" group refers to a saturated aliphatic
hydrocarbon group containing 1-8 (e.g., 1-6 or 1-4) carbon atoms.
An alkyl group can be straight or branched. Examples of an alkyl
group include, but are not limited to, methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,
n-heptyl, and 2-ethylhexyl. An alkyl group can be optionally
substituted with one or more substituents such as alkoxy,
cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy,
aralkyloxy, heteroarylalkoxy, amino, nitro, carboxy, cyano, halo,
hydroxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl,
alkylsulfonyl, aminocarbonyl, alkylcarbonylamino,
cycloalkylcarbonylamino, cycloalkyl-alkylcarbonylamino,
arylcarbonylamino, aralkylcarbonylamino,
heterocycloalkyl-carbonylamino,
heterocycloalkyl-alkylcarbonylamino, heteroarylcarbonylamino,
heteroaralkylcarbonylamino, urea, thiourea, sulfamoyl, sulfamide,
alkoxycarbonyl, or alkylcarbonyloxy. An "alkylene" is a divalent
alkyl group, as defined herein.
As used herein, an "alkenyl" group refers to an aliphatic carbon
group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and at
least one-double bond. Like an alkyl group, an alkenyl group can be
straight or branched. Examples of an alkenyl group include, but are
not limited to allyl, isoprenyl, 2-butenyl, and 2-hexenyl. An
alkenyl group can be optionally substituted with one or more
substituents such as alkoxy, cycloalkyloxy, heterocycloalkyloxy,
aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, amino, nitro,
carboxy, cyano, halo, hydroxy, sulfo, mercapto, alkylsulfanyl,
alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino,
cycloalkylcarbonylamino, cycloalkyl-alkylcarbonylamino,
arylcarbonylamino, aralkylcarbonylamino,
heterocycloalkyl-carbonylamino,
heterocycloalkyl-alkylcarbonylamino, heteroarylcarbonylamino,
heteroaralkylcarbonylamino, urea, thiourea, sulfamoyl, sulfamide,
alkoxycarbonyl, or alkylcarbonyloxy. An "alkenylene" is a divalent
alkenyl group, as defined herein.
As used herein, an "alkynyl" group refers to an aliphatic carbon
group that contains 2-8 (e.g., 2-6 or 24) carbon atoms and has at
least one triple bond. An alkynyl group can be straight or
branched. Examples of an alkynyl group include, but are not limited
to, propargyl and butynyl. An alkynyl group can be optionally
substituted with one or more substituents such as alkoxy,
cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy,
aralkyloxy, heteroarylalkoxy, amino, nitro, carboxy, cyano, halo,
hydroxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl,
alkylsulfonyl, aminocarbonyl, alkylcarbonylamino,
cycloalkylcarbonylamino, cycloalkyl-alkylcarbonylamino,
arylcarbonylamino, aralkylcarbonylamino,
heterocycloalkyl-carbonylamino,
heterocycloalkyl-alkylcarbonylamino, heteroarylcarbonylamino,
heteroaralkylcarbonylamino, urea, thiourea, sulfamoyl, sulfamide,
alkoxycarbonyl, or alkylcarbonyloxy. An "alkynylene" is a divalent
alkynyl group, as defined herein.
As used herein, an "amino" group refers to --NR.sup.XR.sup.Y
wherein each of R.sup.X and R.sup.Y is independently hydrogen,
alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl,
heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, or
heteroaralkyl. When the term "amino" is not the terminal group
(e.g., alkylcarbonylamino), it is represented by --NR.sup.X--.
R.sup.X has the same meaning as defined above.
As used herein, an "aryl" group refers to phenyl, naphthyl, or a
benzofused group having 2 to 3 rings. For example, a benzofused
group includes phenyl fused with one or two C.sub.4-8 carbocyclic
moieties, e.g., 1,2,3,4-tetrahydronaphthyl, indanyl, or fluorenyl.
An aryl is optionally substituted with one or more substituents
such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl
such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl,
(cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl,
heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy,
heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl,
amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy,
aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino,
(cycloalkyl)alkylcarbonylamino, arylcarbonylamino,
aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,
(heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino,
heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto,
alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo,
or carbamoyl.
As used herein, an "aralkyl" group refers to an alkyl group (e.g.,
a C.sub.1-4 alkyl group) that is substituted with an aryl group.
Both "alkyl" and "aryl" have been defined above. An example of an
aralkyl group is benzyl.
As used herein, a "cycloalkyl" group refers to an aliphatic
carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms. Examples of
cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl,
cycloheptyl, adamantyl, norbornyl, cubyl, octahydro-indenyl,
decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl,
bicyclo[3.3.1]nonyl, and bicyclo[3.2.3]nonyl. A "cycloalkenyl"
group, as used herein, refers to a non-aromatic carbocyclic ring of
3-10 (e.g., 4-8) carbon atoms having one or more double bond.
Examples of cycloalkenyl groups include cyclopentenyl,
1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl,
hexahydro-indenyl, octahydro-naphthyl, bicyclo[2.2.2]octenyl, and
bicyclo[3.3.1]nonenyl. A cycloalkyl or cycloalkenyl group can be
optionally substituted with one or more substituents such as alkyl
(including carboxyalkyl, hydroxyalkyl, and haloalkyl such as
trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,
heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl,
alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy,
aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro,
carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl,
alkylcarbonylamino, cycloalkylcarbonylamino,
(cycloalkyl)alkylcarbonylamino, arylcarbonylamino,
aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,
(heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino,
heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto,
alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo,
or carbamoyl.
As used herein, a "heterocycloalkyl" group refers to a 3- to
10-membered (e.g., 4- to 8-membered) saturated ring structure, in
which one or more of the ring atoms is a heteroatom, e.g., N, O, or
S. Examples of a heterocycloalkyl group include piperidinyl,
piperazinyl, tetrahydropyranyl, tetrahydrofuryl, dioxolanyl,
oxazolidinyl, isooxazolidinyl, morpholinyl, octahydro-benzofuryl,
octahydro-chromenyl, octahydro-thiochromenyl, octahydro-indolyl,
octahydro-pyrindinyl, decahydro-quinolinyl,
octahydro-benzo[b]thiophenyl, 2-oxa-bicyclo[2.2.2]octyl,
1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and
2,6-dioxa-tricyclo[3.3.1.0.sup.3,7]nonyl. A "heterocycloalkenyl"
group, as used herein, refers to a 3- to 10-membered (e.g., 4- to
8-membered) non-aromatic ring structure having one or more double
bonds, and wherein one or more of the ring atoms is a heteroatom,
e.g., N, O, or S. A heterocycloalkyl or heterocycloalkenyl group
can be optionally substituted with one or more substituents such as
alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as
trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,
heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl,
alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy,
aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro,
carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl,
alkylcarbonylamino, cycloalkylcarbonylamino,
(cycloalkyl)alkylcarbonylamino, arylcarbonylamino,
aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,
(heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino,
heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto,
alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo,
or carbamoyl.
A "heteroaryl" group, as used herein, refers to a monocyclic,
bicyclic, or tricyclic ring structure having 5 to 15 ring atoms
wherein one or more of the ring atoms is a heteroatom, e.g., N, O,
or S and wherein one or more rings of the bicyclic or tricyclic
ring structure is aromatic. Some examples of heteroaryl are
pyridyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl,
indolyl, tetrazolyl, benzofuryl, benzthiazolyl, xanthene,
thioxanthene, phenothiazine, dihydroindole, and benzo[1,3]dioxole.
A heteroaryl is optionally substituted with one or more
substituents such as alkyl (including carboxyalkyl, hydroxyalkyl,
and haloalkyl such as trifluoromethyl), alkenyl, alkynyl,
cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl,
(heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy,
heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,
heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy,
alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl,
alkylcarbonylamino, cycloalkylcarbonylamino,
(cycloalkyl)alkylcarbonylamino, arylcarbonylamino,
aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,
(heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino,
heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto,
alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo,
or carbamoyl. A "heteroaralkyl" group, as used herein, refers to an
alkyl group (e.g., a C.sub.1-4 alkyl group) that is substituted
with a heteroaryl group. Both "alkyl" and "heteroaryl" have been
defined above.
As used herein, "heterocyclyl" includes heterocycloalkyl,
heterocycloalkenyl, and heteroaryl, each of which has been defined
previously.
As used herein, "cyclic moiety" includes cycloalkyl,
heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and
heteroaryl, each of which has been defined previously.
As used herein, an "acyl" group refers to a formyl group or
alkyl-C(.dbd.O)-- where "alkyl" has been defined previously. Acetyl
and pivaloyl are examples of acyl groups.
As used herein, a "carbamoyl" group refers to a group having the
structure --O--CO--NR.sup.XR.sup.Y or --NR.sup.X--CO--O--R.sup.Z
wherein R.sup.X and R.sup.Y have been defined above and R.sup.Z is
alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl,
heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, or
heteroaralkyl.
As used herein, a "carboxy" and a "sulfo" group refer to --COOH and
--SO.sub.3H, respectively.
As used herein, an "alkoxy" group refers to an alkyl-O-- group
where "alkyl" has been defined previously.
As used herein, a "sulfoxy" group refers to --O--SO--R.sup.X or
--SO--O--R.sup.X, where R.sup.X has been defined above.
As used herein, a "halogen" or "halo" group refers to fluorine,
chlorine, bromine or iodine.
As used herein, a "sulfamoyl" group refers to the structure
--SO.sub.2--NR.sup.XR.sup.Y or --NR.sup.X--SO.sub.2--R.sup.Z
wherein R.sup.X, R.sup.Y, and R.sup.Z have been defined above.
As used herein, a "sulfamide" group refers to the structure
--NR.sup.X--S(O).sub.2--NR.sup.YR.sup.Z wherein R.sup.X, R.sup.Y,
and R.sup.Z have been defined above.
As used herein, a "urea" group refers to the structure
--NR.sup.X--CO--NR.sup.YR.sup.Z and a "thiourea" group refers to
the structure --NR.sup.X--CS--NR.sup.YR.sup.Z. R.sup.X, R.sup.Y,
and R.sup.Z have been defined above.
As used herein, an effective amount is defined as the amount which
is required to confer a therapeutic effect on the treated patient,
and is typically determined based on age, surface area, weight, and
condition of the patient. The interrelationship of dosages for
animals and humans (based on milligrams per meter squared of body
surface) is described by Freireich et al., Cancer Chemother. Rep.,
50: 219 (1966). Body surface area may be approximately determined
from height and weight of the patient. See, e.g., Scientific
Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 537 (1970). As used
herein, "patient" refers to a mammal, including a human.
An antagonist is a molecule that binds to the receptor without
activating the receptor. It competes with the endogenous ligand(s)
or substrate(s) for binding site(s) on the receptor and, thus
inhibits the ability of the receptor to transduce an intracellular
signal in response to endogenous ligand binding.
As compounds of formula (I) are antagonists of the A.sub.2a subtype
of the adenosine receptors, these compounds are useful in
inhibiting the consequences of signal transduction through the
adenosine A.sub.2a receptor. Thus, compounds of formula (I) possess
the therapeutical utility of treating and/or preventing disorders
or diseases for which inhibition of the adenosine A.sub.2a receptor
signaling pathways is desirable (e.g., Parkinson's disease or
depression).
Unless otherwise defined, all technical and scientific terms used
herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. All
publications, patent applications, patents, and other references
mentioned herein are incorporated by reference in their entirety.
In addition, the materials, methods, and examples are illustrative
only and not intended to be limiting.
Other features and advantages of the invention will be apparent
from the following detailed description, and from the claims.
DETAILED DESCRIPTION OF THE INVENTION
Unless otherwise defined, all technical and scientific terms used
herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the present
invention, suitable materials and methods are described below. All
publications, patent applications, patents, and other references
mentioned herein are incorporated by reference in their entirety.
In addition, the materials, methods, and examples are illustrative
only and are not intended to be limiting.
Synthesis of the Adenosine Antagonist Compounds
Compounds of formula (I) may be prepared by a number of known
methods from commercially available or known starting
materials.
In one method, a compound of formula (I) is prepared according to
the method outlined in Scheme 1 below. Specifically, the method
utilizes a sulfone starting material (II) or a chloro (or other
halo groups) starting material (III). The sulfone starting material
(II), wherein B, B.sup.1, and B.sup.2 are N and X.sup.1 is a bond,
can be prepared according to known methods, e.g., see Caulkett et
al., J. Chem. Soc. Perkin Trans I. 801-808 (1995) and de Zwart et
al., Drug Dev. Res. 48:95-103 (1999). The chloro starting material
(III) (wherein B is N or C, either B.sup.1 or B.sup.2 is N, and
X.sup.1 is a bond) can also be prepared according to known methods,
see, e.g., U.S. Pat. No. 6,222,035 and WO 99/43678. See also Kranz,
E. et al., Chemische Berichte 105:388-405 (1972) and Marei, M. G.,
Bulletin of the Chemical Society of Japan 66:1172-1175 (1993). As
apparent to a skilled person in the art, starting materials wherein
X.sup.1 is not a bond (e.g., X.sup.1 is an alkynylene) can be
prepared by many known methods. For example, one can react the
sulfone starting material (II) wherein X.sup.1 is a bond (e.g.,
2-furan-2-yl-5-methanesulfonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yla-
mine) with an appropriate nucleophile, e.g., methylsulfanylethyne
or chloroethyne, to form an intermediate with a methylsulfanyl or a
chloro group, respectively. The intermediate with a methylsulfanyl
group can be further modified by, e.g., oxidation of the
methylsulfanyl group to methylsulfonyl group to form a starting
material (II) wherein X.sup.1 is an alkynylene.
According to the method depicted in Scheme 1, the starting material
(II) or (III) can react with a bicyclic diamine compound L (e.g.,
2,5-diaza-bicyclo[2.2.1]heptane) to form an intermediate (IV). The
reaction can be carried out in an appropriate solvent such as
acetonitrile (CH.sub.3CN), dimethyl sulfoxide (DMSO), or
N,N-dimethylformamide (DMF) at a temperature ranging from about
80.degree. C. to about 120.degree. C. The intermediate (IV) can
further react, via the free amino group of moiety L, with a
compound of the formula R.sup.1--Y--X.sup.2-LG (where R.sup.1, Y,
and X.sup.2 have been defined above and LG represents an
appropriate leaving group such as halide, mesylate, or tosylate) to
form a desired compound of formula (I). See Route (A) below and
Examples 13 and 15.
Alternatively, the intermediate (IV) can react with an appropriate
aldehyde or carboxylic acid to form an amide, which can then
undergo reductive amination to form a desired compound of formula
(I). Examples of a typical reducing agent used in this reaction are
sodium cyanoborohydride and sodium triacetoxyborohydride. See Route
(B) below and Example 14.
Still another alternative method involves reacting the intermediate
(IV) with an appropriate epoxide to form a desired compound of
formula (I). See Route (C) below. Note that the reaction between
moiety L and the epoxide ring leads to opening of the ring, thus
forming a hydroxy-containing moiety X.sup.2. Moiety X.sup.2a and
hydroxyethylene group (from the epoxide ring) together form moiety
X.sup.2 (see route (C) shown in Scheme 1 below).
##STR00009##
In another method, a compound of formula (I) can be prepared by
reacting the starting material of formula (II) or formula (III)
with a compound of the formula Y'--X.sup.2-L', where L' and Y' are
the precursor of moieties L and Y, respectively. For example, the
compound Y'--X.sup.2-L' can be a hydroxyalkyl substituted bicyclic
compound with a nitrogen ring atom (e.g.,
(octahydro-pyrido[1,2-a]pyrazin-7-yl)-methanol). Note that a
compound of the formula Y'--X.sup.2-L' can be prepared by known
methods, see, e.g., Bright and Desai, U.S. Pat. No. 5,122,525 and
Urban, J. Heterocyclic Chem. 32: 857 (1995). The free amine of the
bicyclic ring can react with the sulfone or halo group of the
starting material (II) or (III) to form the intermediate (V). The
hydroxy group of moiety Y' can undergo further modification and
then react with a compound R.sup.1' (the precursor of moiety
R.sup.1) to form a compound of formula (I). For example, Y' can be
converted from a hydroxyl group to a mesylate or a tosylate group,
which can react with a compound R.sup.1' (e.g., a phenol or a
piperidine) to form a compound of formula (I). See Scheme 2, route
(1) below and Example 5. As another example, Y' can be converted
from a hydroxyl group to tin amine group, which can undergo further
transformations, e.g., according to route (A), (B), or (C) as shown
in Scheme 1, to form a compound of formula (I). See Scheme 2, route
(2) below and Examples 9-12.
##STR00010## ##STR00011##
In a further method, the compound of the formula L'-X.sup.1'
(wherein L' and X.sup.1' are precursors of moiety L and X.sup.1,
respectively) can couple to a compound R.sup.1--Y--X.sup.2'
(wherein X.sup.2' is the precursor of moiety X.sup.2) to form a
compound of the formula R.sup.1--Y--X.sup.2-L-X.sup.1' prior to
reacting with a starting material of formula (II) or formula (III).
For example, the compound L'-X.sup.1' can be a hydroxyalkyl
substituted bicyclic compound with a nitrogen ring atom (e.g.,
(octahydro-pyrido[1,2-a]pyrazin-6-yl)-methanol), which can react
with a halo-substituted aralkyl (e.g., 2,4-difluorobenzylbromide)
to form a compound of the formula R.sup.1--Y--X.sup.2-L-X.sup.1'
(e.g.,
[2-(2,4-difluoro-benzyl)-octahydro-pyrido[1,2-a]pyrazin-6-yl]-methanol,
wherein Y is a bond). This compound of the formula
R.sup.1--Y--X.sup.2-L-X.sup.1' can be further modified to convert
the hydroxyl group into an amine group (e.g.,
C-[2-(2,4-difluoro-benzyl)-octahydro-pyrido[1,2-a]pyrazin-6-yl]-methylami-
ne), which can react with a starting material (II) or (III) to
yield a compound of formula (I). See Scheme 3 and Example 6
below.
##STR00012##
As can be appreciated by the skilled artisan, the above synthetic
schemes are exemplary and not intended to comprise a comprehensive
list of all means by which the compounds described and claimed in
this application may be synthesized. For example, the reaction
steps shown in the schemes above can be conducted in a different
order, e.g., by reacting a compound of the formula Y--X.sup.2-L
with the sulfone or chloride starting material before coupling with
R.sup.1. Further methods will be evident to those of ordinary skill
in the art.
For reference on protecting groups, see, e.g., Greene and Wutts:
Protective Groups in Organic Synthesis, 3.sup.rd edition, John
Wiley & Sons (1999).
Uses for the A.sub.2a Adenosine Antagonist Compounds
Compounds of the invention are useful in the prevention and/or
treatment of various neurological diseases and disorders whose
causes or symptoms are mediated by the A.sub.2a adenosine receptor
signaling pathways. Such diseases and disorders include Parkinson's
disease and related neurodegenerative disorders, depression,
anxiety, and cerebrovascular disorders such as migraine. In
addition, compositions of the invention are useful for
neuroprotection, i.e., to prevent or inhibit neuronal death or
degeneration associated with conditions such as Alzheimer's
disease, stroke (cerebral ischemia), and brain trauma.
Administration of Compounds of the Invention
Compounds of the invention can be administered to an animal,
preferably a mammal, e.g., a human, non-human primate, dog, pig,
sheep, goat, cat, mouse, rat, guinea pig, rabbit, hamster, or
marmoset. The compounds can be administered in any manner suitable
for the administration of pharmaceutical compounds, including, but
not limited to, pills, tablets, capsules, aerosols, suppositories,
liquid formulations for ingestion or injection or for use as eye or
ear drops, dietary supplements, and topical preparations. The
compounds can be administered orally, intranasally, transdermally,
intradermally, vaginally, intraaurally, intraocularly, buccally,
rectally, transmucosally, or via inhalation, implantation (e.g.,
surgically), or intravenous administration.
Pharmaceutical Compositions
Compounds of the invention can be formulated into pharmaceutical
compositions for administration to animals, including humans. These
pharmaceutical compositions preferably include a pharmaceutically
acceptable carrier and an amount of A.sub.2a adenosine receptor
antagonist effective to improve neurological functions such as
motor functions and cognitive functions.
Pharmaceutically acceptable carriers useful in these pharmaceutical
compositions include, e.g., ion exchangers, alumina, aluminum
stearate, lecithin, serum proteins, such as human serum albumin,
buffer substances such as phosphates, glycine, sorbic acid,
potassium sorbate, partial glyceride mixtures of saturated
vegetable fatty acids, water, salts or electrolytes, such as
protamine sulfate, disodium hydrogen phosphate, potassium hydrogen
phosphate, sodium chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, cellulose-based substances,
polyethylene glycol, sodium carboxymethylcellulose, polyacrylates,
waxes, polyethylene-polyoxypropylene-block polymers, polyethylene
glycol and wool fat.
The compositions of the present invention can be administered
parenterally, orally, by inhalation spray, topically, rectally,
nasally, buccally, vaginally or via an implanted reservoir. The
term "parenteral" as used herein includes subcutaneous,
intravenous, intramuscular, intra-articular, intra-synovial,
intrasternal, intrathecal, intrahepatic, intralesional and
intracranial injection or infusion techniques. Preferably, the
compositions are administered orally, intraperitoneally or
intravenously.
Sterile injectable forms of the compositions of this invention can
be aqueous or oleaginous suspension. These suspensions may be
formulated according to techniques known in the art using suitable
dispersing or wetting agents and suspending agents. The sterile
injectable preparation can also be a sterile injectable solution or
suspension in a non-toxic parenterally-acceptable diluent or
solvent, for example as a solution in 1,3-butanediol. Among the
acceptable vehicles and solvents that can be employed are water,
Ringer's solution and isotonic sodium chloride solution. In
addition, sterile, fixed oils are conventionally employed as a
solvent or suspending medium. For this purpose, any bland fixed oil
can be employed including synthetic mono- or di-glycerides. Fatty
acids, such as oleic acid and its glyceride derivatives are useful
in the preparation of injectables, as are natural
pharmaceutically-acceptable oils, such as olive oil or castor oil,
especially in their polyoxyethylated versions. These oil solutions
or suspensions also can contain a long-chain alcohol diluent or
dispersant, such as carboxymethyl cellulose or similar dispersing
agents which are commonly used in the formulation of
pharmaceutically acceptable dosage forms including emulsions and
suspensions. Other commonly used surfactants, such as Tweens, Spans
and other emulsifying agents or bioavailability enhancers which are
commonly used in the manufacture of pharmaceutically acceptable
solid, liquid, or other dosage forms also can be used for the
purposes of formulation.
Parenteral formulations can be a single bolus dose, an infusion or
a loading bolus dose followed with a maintenance dose. These
compositions can be administered once a day or on an "as needed"
basis.
The pharmaceutical compositions of this invention be administered
orally in any orally acceptable dosage form including, capsules,
tablets, aqueous suspensions or solutions. In the case of tablets
for oral use, carriers commonly used include lactose and corn
starch. Lubricating agents, such as magnesium stearate, are also
typically added. For oral administration in a capsule form, useful
diluents include lactose and dried cornstarch. When aqueous
suspensions are required for oral use, the active ingredient is
combined with emulsifying and suspending agents. If desired,
certain sweetening, flavoring or coloring agents can also be
added.
Alternatively, the pharmaceutical compositions of this invention
may be administered in the form of suppositories for rectal
administration. These can be prepared by mixing the agent with a
suitable non-irritating excipient which is solid at room
temperature but liquid at rectal temperature and therefore will
melt in the rectum to release the drug. Such materials include
cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of this invention may also be
administered topically. Topical application can be effected in a
rectal suppository formulation (see above) or in a suitable enema
formulation. Topically-transdermal patches may also be used.
For topical applications, the pharmaceutical compositions can be
formulated in a suitable ointment containing the active component
suspended or dissolved in one or more carriers. Carriers for
topical administration of the compounds of this invention include,
mineral oil, liquid petrolatum, white petrolatum, propylene glycol,
polyoxyethylene, polyoxypropylene compound, emulsifying wax and
water. Alternatively, the pharmaceutical compositions can be
formulated in a suitable lotion or cream containing the active
components suspended or dissolved in one or more pharmaceutically
acceptable carriers. Suitable carriers include, but are not limited
to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl
esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and
water.
For ophthalmic use, the pharmaceutical compositions may be
formulated as micronized suspensions in isotonic, pH adjusted
sterile saline, or, preferably, as solutions in isotonic, pH
adjusted sterile saline, either with or without a preservative such
as benzylalkonium chloride. Alternatively, for ophthalmic uses, the
pharmaceutical compositions may be formulated in an ointment such
as petrolatum.
The pharmaceutical compositions of this invention also can be
administered by nasal aerosol or inhalation. Such compositions can
be prepared according to techniques known in the art of
pharmaceutical formulation, and can be prepared as solutions in
saline, employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability, fluorocarbons,
and/or other conventional solubilizing or dispersing agents.
The amount of A.sub.2a adenosine receptor antagonist that may be
combined with the carrier materials to produce a single dosage form
will vary depending upon the host treated and the particular mode
of administration. The compositions can be formulated so that a
dosage of between 0.01-100 mg/kg body weight of the A.sub.2a
adenosine receptor antagonist is administered to a patient
receiving these compositions. In some embodiments of the invention,
the dosage is 0.1-10 mg/kg body weight. The composition may be
administered as a single dose, multiple doses or over an
established period of time in an infusion.
A specific dosage and treatment regimen for any particular patient
will depend upon a variety of factors, including the particular
A.sub.2a adenosine receptor antagonist, the patient's age, body
weight, general health, sex, and diet, and the time of
administration, rate of excretion, drug combination, and the
severity of the particular disease being treated. Judgment of such
factors by medical caregivers is within ordinary skill in the art.
The amount of antagonist will also depend on the individual patient
to be treated, the route of administration, the type of
formulation, the characteristics of the compound used, the severity
of the disease, and the desired effect. The amounts of antagonist
can be determined by pharmacological and pharmacokinetic principles
well-known in the art.
The invention will be further described in the following examples,
which do not limit the scope of the invention described in the
claims.
In the following examples, unless indicated otherwise, all
commercial reagents were obtained from Sigma-Aldrich (St. Louis,
Mo.), Lancaster (Windham N.H.), Acros (Pittsburgh, Pa.), Alfa
(Berkshire, UK), TCI (Portland, Oreg.), or Maybridge (Cornwall,
UK).
EXAMPLE 1
(7RS,9aRS)-[2-(7-Amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-
-yl)-octahydro-pyrido[1,2-a]pyrazin-7-yl]-methanol
2-Furan-2-yl-5-methanesulfonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yla-
mine (1 eq.; for reference, see J. Chem. Soc. Perkin Trans. 1, 801
(1995)) and cis-(octahydro-pyrido[1,2-a]pyrazin-7-yl)-methanol (1-2
eq; see U.S. Pat. No. 5,122,525) were dissolved in DMSO. The
mixture was stirred at around 80.degree. C. for 2 hours. The
solution was then cooled to room temperature, filtered and purified
by preparative HPLC using aqueous CH.sub.3CN solution (buffered
with 0.1% TFA) to give the desired compound as a white solid.
Alternatively, for scale up synthesis, the DMSO solvent was removed
and the crude product was chromatographed on silica gel column
using 5-10% MeOH/CH.sub.2Cl.sub.2 as eluant to afford the desired
product. .sup.1H NMR (400 Hz, CD.sub.3OD) .delta. 7.70 (d, J=2.0
Hz, 1H), 7.12 (d, J=3.5 Hz, 1H), 6.62 (dd, J=3.5, 2.0 Hz, 1H), 4.75
(d, J=12.0 Hz, 1H), 4.65 (d, J=12.5 Hz, 1H), 3.82 (dd, J=10.5, 7.5
Hz, 1H), 3.74 (dd, J=10.5, 7.5 Hz, 1H), 3.11 (dt, J=13.0, 3.0 Hz,
1H), 2.93 (d, J=11.5 Hz, 1H), 2.78 (d, J=11.5 Hz, 1H), 2.68 (dd,
J=13.0, 10.5 Hz, 1H), 2.22 (dd, J=11.5, 3.0 Hz, 1H), 2.14 (dt,
J=12.0, 3.0 Hz, 1H), 1.93 (m, 1H), 1.85 (brd, J=12.0 Hz, 2H), 1.60
(m, 1H), 1.43 (m, 2H). MS m/z: 371 [M+H].sup.+.
EXAMPLE 2
(6RS,9aRS)-[2-(7-Amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-
-yl)-octahydro-pyrido[1,2-a]pyrazin-6-yl]-methanol
(6RS,9aRS)-[2-(7-Amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin--
5-yl)-octahydro-pyrido[1,2-a]pyrazin-6-yl]-methanol was prepared in
the same manner as described in Example 1, except that
cis-(octahydro-pyrido[1,2-a]pyrazin-6-yl)-methanol (see WO
90/08144) was used as the starting material instead of
cis-(octahydro-pyrido[1,2-a]pyrazin-7-yl)-methanol. The desired
product was obtained as a white solid: .sup.1H NMR (400 Hz,
CD.sub.3OD) .delta. 7.75 (d, J=2.0 Hz, 1H), 7.18 (d, J=3.5 Hz, 1H),
6.65 (dd, J=3.5, 2.0 Hz, 1H), 5.08 (brd, J=15.0 Hz, 1H), 4.94 (brd,
J=15.0 Hz, 1H), 4.08 (dd, J=12.0, 3.5 Hz, 1H), 3.90 (brd, J=12.0
Hz, 1H), 3.62 (brd, J=12.5 Hz, 1H), 3.36 (m, 2H), 3.16 (m, J=3H),
2.75 (t, J=12.0 Hz, 1H), 1.98 (m, 4H), 1.67 (m, 2H). MS m/z: 371
[M+H].sup.+.
EXAMPLE 3
(7RS,9aRS)-[2-(5-Amino-2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)--
octahydro-pyrido[1,2-a]pyrazin-7-yl]-methanol
7-Chloro-2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine (1
eq, see U.S. Pat. No. 6,222,035 B1),
cis-(octahydro-pyrido[1,2-a]pyrazin-7-yl)-methanol (1-2 eq.), and
CsF (1-2 eq.) were dissolved in DMSO. The mixture was stirred at
around 120.degree. C. for 18 hours. The solution was then cooled to
room temperature, filtered and purified by preparative HPLC using
aqueous CH.sub.3CN (buffered with 0.1% TFA) to give the desired,
compound as a white solid. Alternatively, for scale up synthesis,
the DMSO solvent was removed and the crude product was
chromatographed on silica gel column using 5-10%
MeOH/CH.sub.2Cl.sub.2 as eluant to afford the desired product:
.sup.1H NMR (400 Hz, CD.sub.3OD) .delta. 7.71 (d, J=2.0 Hz, 1H),
7.14 (d, J=3.5 Hz, 1H), 6.63 (dd, J=3.5, 2.0 Hz, 1H), 5.99 (s, 1H),
4.26 (d, J=13.5 Hz, 1H), 4.19 (d, J=13.5 Hz, 1H), 3.83 (dd, J=10.5,
7.5 Hz, 1H), 3.74 (dd, J=10.5, 7.5 Hz, 1H), 3.04 (dt, J=12.5, 3.0
Hz, 1H), 2.95 (d, J=12.0 Hz, 1H), 2.80 (d, J=11.0 Hz, 1H), 2.62
(dd, J=12.5, 10.5 Hz, 1H), 2.22 (m, 2H), 1.98 (m, 1H), 1.86 (brd,
12.0 Hz, 2H), 1.62 (m, 1H), 1.50-1.42 (m, 2H). MS m/z: 370
[M+H].sup.+.
EXAMPLE 4
(7RS,9aRS)-[2-(7-Amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)--
octahydro-pyrido[1,2-a]pyrazin-7-yl]-methanol
5-chloro-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrimidin-7-ylamine (1
eq; see WO 99/43678 A1),
cis-(octahydro-pyrido[1,2-a]pyrazin-7-yl)-methanol (1-2 eq), and
CsF (1-2 eq) were dissolved in DMSO. The mixture was stirred at
around 100.degree. C. for 18 hours. The solution was then cooled to
room temperature, filtered, and purified by preparative HPLC using
aqueous CH.sub.3CN (buffered with 0.1% TFA) to give the desired
compound as a white solid. Alternatively, for scale up synthesis,
the DMSO solvent was removed and the crude product was
chromatographed on silica gel column using 5-10%
MeOH/CH.sub.2Cl.sub.2 as eluant to afford the desired product:
.sup.1H NMR (400 Hz, CD.sub.3OD) .delta. 7.69 (d, J=2.3 Hz, 1H),
7.10 (d, J=3.5 Hz, 1H), 6.61 (dd, J=3.5, 2.3 Hz, 1H), 5.73 (s, 1H),
4.32 (d, J=13.5 Hz, 1H), 4.24 (d, J=13.5 Hz, 1H), 3.82 (dd, J=10.5,
7.5 Hz, 1H), 3.74 (dd, J=10.5, 7.5 Hz, 1H), 3.10 (dt, J=12.5, 3.2
Hz, 1H), 2.94 (d, J=11.5 Hz, 1H), 2.79 (d, J=11.5 Hz, 1H), 2.67
(dd, J=13.0, 10.5 Hz, 1H), 2.21 (m, 2H), 1.96 (m, 1H), 1.85 (brd,
12.0 Hz, 2H), 1.60 (m, 1H), 1.47 (m, 2H). MS m/z: 370
[M+H].sup.+.
EXAMPLE 5
(7RS,9aSR)-5-[7-(3-Fluoro-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazin-2--
yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine
Synthesis of the title compound is described in parts (a) and (b)
below.
(a) Methanesulfonic acid
2-(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)-octahy-
dro-pyrido[1,2-a]pyrazin-7-ylmethyl ester
A solution containing
(7RS,9aSR)-[2-(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin--
5-yl)-octahydro-pyrido[1,2-a]pyrazin-7-yl]-methanol (1 eq.; see
Example 1 above) and triethyl amine (4 eq.) in DMF was treated with
methansulfonyl chloride (2 eq.) at around 0.degree. C. After 2
hours, the reaction was quenched with ice, treated with 1M NaOH,
and the mixture was extracted with methylene chloride. The combined
organic layers was washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated to give the corresponding mesylate,
which was used in the next step without further purification.
(b)
(7RS,9aSR)-5-[7-(2-Fluoro-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazi-
n-2-yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine
A solution containing 3-fluorophenol (1.5 eq.) in DMF was treated
with sodium hydride (60% oil dispersion, 4 eq.) for 2 hours at
around 50.degree. C. A solution containing containing
methanesulfonic acid
2-(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)-octahy-
dro-pyrido[1,2-a]pyrazin-7-ylmethyl ester (1 eq., see subpart (a)
above) in DMF was added. The resulting mixture was then heated at
around 100.degree. C. for 24 hours. The solvent was removed, and
the residue was dissolved in DMSO, filtered and purified by
preparative HPLC using aqueous CH.sub.3CN (buffered with 0.1% TFA)
to afford the desired product as a white powder: .sup.1H NMR (400
Hz, DMSO-d6) .delta. 7.96 (d, J=2.0 Hz, 1H), 7.39 (m, 1H), 7.15 (d,
J=3.0 Hz, 1H), 6.92-6.83 (m, 3H), 6.75 (dd, J=3.0, 2.0 Hz, 1H),
4.84 (m, 2H), 4.08 (dd, J=10.0, 5.0 Hz, 1H), 3.74 (dd, J=10.0, 7.0
Hz, 1H), 3.65 (m, 2H), 3.33 (m, 3H), 3.10 (m, 1H), 2.97 (m, 1H),
2.39 (m, 1H), 1.99 (m, 2H), 1.67 (m, 1H), 1.48 (m, 1H). MS m/z: 465
[M+H].sup.+.
EXAMPLE 6
(7RS,9aRS)-2-Furan-2-yl-N.sup.5-(2-pyrimidin-2-yl-octahydro-pyrido[1,2-a]p-
yrazin-7-ylmethyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine
Synthesis of the title compound is described in parts (a)-(d)
below.
(a)
Cis-(2-pyrimidin-2-yl-octahydro-pyrido[1,2-a]pyrazin-7-yl)-methanol
Cis-(octahydro-pyrido[1,2-a]pyrazin-7-yl)-methanol (1 eq),
2-chloro-pyrimidine (1 eq.), and Na.sub.2CO.sub.3 (1 eq.) were
dissolved in water. The mixture was stirred at around 95.degree. C.
for overnight. The solution was cooled to room temperature and
extracted with methylene chloride. The combined organic layers was
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated to give
cis-(2-pyrimidin-2-yl-octahydro-pyrido[1,2-a]pyrazin-7-yl)-methanol
as a white solid. This material was used in the next step without
further purification.
(b) Methanesulfonic acid
2-pyrimidin-2-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl
ester
A solution of
cis-(2-pyrimidin-2-yl-octahydro-pyrido[1,2-a]pyrazin-7-yl)-methanol
(1 eq., see subpart (a) above) and triethyl amine (2 eq.) in
CH.sub.2Cl.sub.2 was treated with methansulfonyl chloride (1.5 eq.)
at around 0.degree. C. for 20 minutes. The reaction was quenched
with aqueous Na.sub.2CO.sub.3 solution (2 M), and the mixture was
extracted with methylene chloride. The combined organic layers was
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated to give the corresponding mesylate as yellow oil. This
material was used in the next step without further
purification.
(c)
7-Azidomethyl-2-pyrimidin-2-yl-octahydro-pyrido[1,2-a]pyrazine
A solution containing methanesulfonic acid
2-pyrimidin-2-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl ester (1
eq., see subpart (b) above) and sodium azide (2 eq.) in DMF was
stirred at around 90.degree. C. for 24 hours. The solution was
cooled to room temperature, diluted with water, and extracted with
methylene chloride. The combined organic layers was washed with
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated to
give the corresponding azide as yellow oil. This material was used
in the next step without further purification.
(d)
(7RS,9aSR)-2-Furan-2-yl-N.sup.5-(2-pyrimidin-2-yl-octahydro-pyrido[1,2-
-a]pyrazin-7-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-5,7-diamine
A suspension of the azide (1 eq., see subpart (c) above) and
polymer supported PPh.sub.3 (4 eq., 3 mmol/g loading) in THF was
shaken at room temperature for overnight. Water was then added, and
the resulting mixture was shaken at room temperature for 2 hours.
The suspension was filtered, and the filtered cake was washed with
THF and water. The filtrate was lyophilized to give the
corresponding amine as yellow oil. This material was coupled,
without further purification, to
2-furan-2-yl-5-methanesulfonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yla-
mine in accordance with Example 1 to afford the desired compound:
.sup.1H NMR (400 Hz, DMSO-d6) .delta. 8.52 (d, J=5.0 Hz, 1H), 7.94
(brs, 1H), 7.10 (d, J=3.0 Hz, 1H), 6.84 (t, J=5.0 Hz, 1H), 6.75
(dd, J=3.0, 1.0 Hz, 1H), 4.84 (m, 2H), 3.64-3.19 (m, 8H), 3.13 (m,
1H), 2.30 (m, 1H), 1.88 (m, 2H), 1.80 (m, 2H). MS m/z: 447
[M+H].sup.+.
EXAMPLE 7
(7RS,9aSR)--N.sup.5-[2-(5-Chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-y-
lmethyl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl]-2-furan-2-yl-[1,2,4]tr-
iazolo[1,5-a][1,3,5]triazine-5,7-diamine
Synthesis of the title compound is described in parts (a)-(c)
below.
(a)
Trans-7-Hydroxymethyl-octahydro-pyrido[1,2-a]pyrazine-2-carboxylic
acid tert-butyl ester
To a solution of
trans-(octahydro-pyrido[1,2-a]pyrazin-7-yl)-methanol (1 eq) in
1,4-dioxane was added aqueous KOH solution (5 N) until the pH value
reached 9. A solution of Boc.sub.2O (2 eq.) in 1,4-dioxane was then
added. The mixture was stirred at room temperature for overnight,
after which the solvent was removed, and the residue was diluted
with water, and extracted with methylene chloride. The combined
organic phases were washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated to afford
7-hydroxymethyl-octahydro-pyrido[1,2-a]pyrazine-2-carboxylic acid
tert-butyl ester as a white solid. This material was used in the
next step without further purification.
(b)
Trans-7-[(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5--
ylamino)-methyl]-octahydro-pyrido[1,2-a]pyrazine-2-carboxylic acid
tert-butyl ester
7-Hydroxymethyl-octahydro-pyrido[1,2-a]pyrazine-2-carboxylic acid
tert-butyl ester (see subpart (a) above), was converted to the
corresponding mesylate, azide and amine sequentially according to
Example 6, subparts (b)-(d) above. The corresponding amine was
coupled to
2-furan-2-yl-5-methanesulfonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yla-
mine in accordance to Example 1 to afford
trans-7-[(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yla-
mino)-methyl]-octahydro-pyrido[1,2-a]pyrazine-2-carboxylic acid
tert-butyl ester as yellow oil. This material was used in the next
step without further purification.
(c)
(7RS,9aSR)--N.sup.5-[2-(5-Chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-
-4-ylmethyl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl]-2-furan-2-yl-[1,2,-
4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine
To a solution of
trans-7-[(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yla-
mino)-methyl]-octahydro-pyrido[1,2-a]pyrazine-2-carboxylic acid
tert-butyl ester (1 eq., see subpart (b) above) in methylene
chloride was added trifluoroacetic acid to reach a final
concentration of 10% TFA. The mixture was stirred at room
temperature for 2 hours, after which the solvent was removed under
reduced pressure, and the residue was dissolved in methylene
chloride. To this solution was added
5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazolen-4-carbaldehyde (1
eq.), sodium triacetoxyborohydride (1.5 eq.), and acetic acid (1.5
eq.). The reaction was stirred at room temperature for overnight.
The solvent was then removed, and the residue was purified by
preparative HPLC using aqueous CH.sub.3CN (buffered with 0.1% TFA)
to afford
(7RS,9aSR)--N5-[2-(5-Chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmet-
hyl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl]-2-furan-2-yl-[1,2,4]triazo-
lo[1,5-a][1,3,5]triazine-5,7-diamine. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.70 (d, J=5.0 Hz, 1H), 7.12 (d, J=3.6 Hz,
1H), 6.62 (m, 1H), 4.51 (s, 3H), 4.50 (s, 2H), 3.39-3.53 (m, 4H),
3.00-3.12 (m, 4H), 2.80-2.86 (m, 1H), 2.37-2.43 (m, 1H), 2.21-2.27
(m, 2H), 1.94-1.97 (m, 2H), 1.53-1.58 (m, 1H), 1.30-1.44 (m, 1H).
MS m/z=568 (M.sup.++H).
EXAMPLE 8
(7RS,9aSR)-2-Furan-2-yl-N.sup.5-(2-pyrimidin-2-yl-octahydro-pyrido[1,2-a]p-
yrazin-7-ylmethyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine
To a solution of
trans-7-[(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yla-
mino)-methyl]-octahydro-pyrido[1,2-a]pyrazine-2-carboxylic acid
tert-butyl ester (1 eq., see Example 7(b) above) in methylene
chloride was added trifluoroacetic acid to reach a final
concentration of 10% TFA. The mixture was stirred at room
temperature for 2 hours, after which the solvent was removed under
reduced pressure, and the residue was dissolved in acetonitrile. To
the resulting solution was added 2-chloropyrimidine (1 eq.) and
Na.sub.2CO.sub.3 (2 eq.). The mixture was stirred at around
80.degree. C. for overnight. The solvent was removed afterwards,
and the residue was purified by preparative HPLC using aqueous
CH.sub.3CN (buffered with 0.1% TFA) to afford
(7RS,9aSR)-2-furan-2-yl-N.sup.5-(2-pyrimidin-2-yl-octahydro-pyrido[1,2-a]-
pyrazin-7-ylmethyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine.
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.39 (d, J=4.7 Hz, 2H), 7.70
(d, J=2 Hz, 1H), 7.12 (d, J=3.6 Hz, 1H), 6.72 (t, J=4.7 Hz, 1H),
6.62 (dd, J=2, 3.6 Hz, 1H), 4.97 (d, J=14.1 Hz, 2H), 3.34-3.58 (m,
4H), 3.11-3.24 (m, 3H), 2.82-3.03 (m, 2H), 2.33 (m, 1H), 2.10 (d,
J=14.1 Hz, 1H), 2.02 (d, J=13.2 Hz, 1H), 1.60-1.69 (m, 1H),
1.39-1.49 (m, 1H). MS m/z: 448[M+H].sup.+.
EXAMPLE 9
(7RS,9aRS)-5-(7-Aminomethyl-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-
-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine
A solution of
(7RS,9aRS)-[2-(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin--
5-yl)-octahydro-pyrido[1,2-a]pyrazin-7-yl]-methanol (1 eq.; see
Example 1 above) and triethyl amine (2 eq.) in DMF was treated with
methansulfonyl chloride (2 eq.) at around 0.degree. C. for 30
minutes. The reaction was then warmed to room temperature. To the
reaction solution was added sodium azide (5 eq), and the resulting
mixture was stirred at around 100.degree. C. for 24 hours. The
solvent was then removed, and the residue was purified by silica
gel column chromatography using 5% MeOH/CH.sub.2Cl.sub.2 to afford
the corresponding azide. The azide (1.5 mmol) was subsequently
reduced to the corresponding amine in accordance to Example 6(d).
The amine was then purified by preparative HPLC using aqueous
CH.sub.3CN (buffered with 0.1% TFA) to afford
(7RS,9aRS)-5-(7-aminomethyl-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan--
2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine as a white
powder: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.68-2.28 (m,
4H); 2.30 (m, 1H); 3.13-3.69 (m, 9H), 4.67-4.79 (m, 2H); 6.69 (dd,
J=1.8, 3.4 Hz, 1H); 7.07 (d, J=3.4 Hz); 7.88 (d, J=1.8 Hz), 7.97
(m, 3H), 8.49 (m, 2H). MS m/z: 370 [M+H].sup.+.
EXAMPLE 10
(7RS,9aRS)-5-{7-[(Bis-pyridin-4-ylmethyl-amino)-methyl]-octahydro-pyrido[1-
,2-a]pyrazin-2-yl}-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yla-
mine
A solution of
(7RS,9aRS)-5-(7-aminomethyl-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan--
2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (1 eq.; see
Example 9 above) and pyridine-4-carbaldehyde (3 eq.) in
dichloroethene was treated with sodium triacetoxyborohydride (3
eq.) and AcOH (3 eq.). The mixture was shaken at room temperature
for 24 hours. The solvent was then removed, and the residue was
purified by preparative HPLC using aqueous CH.sub.3CN (buffered
with 0.1% TFA) to afford
(7RS,9aRS)-5-{7-[(bis-pyridin-4-ylmethyl-amino)-methyl]-octahydro-pyrido[-
1,2-a]pyrazin-2-yl}-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yl-
amine as a white powder: .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 1.01-1.32 (m, 1H), 1.50-2.49 (m, 4H), 2.55-3.45 (m, 9H),
3.57-4.03 (m, 4H), 4.55-4.79 (m, 2H), 6.70 (dd, J=1.8, 3.3 Hz, 1H),
7.08 (d, J=3.3 Hz, 1H), 7.76 (d, J=4.5 Hz, 4H), 7.89 (d, J=1.8 Hz,
1H), 8.43-8.62 (m, 2H), 8.73 (d, J=4.5 Hz, 4H). MS m/z: 552
[M+H].sup.+.
EXAMPLE 11
(7RS,9aRS)-2-Furan-2-yl-5-[7-(pyrimidin-2-ylaminomethyl)-octahydro-pyrido[-
1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine
A solution of
(7RS,9aRS)--S-(7-aminomethyl-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan-
-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (1 eq.; see
Example 9 above) and 2-chloropyrimidine (2 eq.) in DMSO was treated
with K.sub.2CO.sub.3 (2 eq.). The mixture was stirred at around
85.degree. C. for 4 hours. The reaction mixture was then filtered,
and the filtrate was concentrated and purified by preparative HPLC
using aqueous CH.sub.3CN (buffered with 0.1% TFA) to afford
(7RS,9aRS)-2-furan-2-yl-5-[7-(pyrimidin-2-ylaminomethyl)-octahydro-pyrido-
[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine
as a white powder: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
1.60-1.86 (m, 4H), 2.21-2.30 (bs, 1H), 3.05-3.32 (m, 4H), 3.33-3.52
(m, 4H), 3.56-3.72 (m, 1H), 4.62-4.83 (m, 2H), 6.63 (t, J=4.8 Hz,
1H), 6.69 (dd, J=1.8, 3.4 Hz, 1H), 7.08 (d, J=3.4 Hz, 1H), 7.41 (t,
J=5.6 Hz, 1H), 7.89 (d, J=1.8 Hz, 1H), 8.32 (d, J=4.8 Hz, 2H),
8.40-8.65 (m, 2H). MS m/z: 448 [M+H].sup.+.
EXAMPLE 12
(7RS,9aRS)-2-Furan-2-yl-5-(7-{[(pyridin-4-ylmethyl)-amino]-methyl}-octahyd-
ro-pyrido[1,2-a]pyrazin-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylami-
ne
A solution of
(7RS,9aRS)-5-(7-aminomethyl-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan--
2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (1 eq.; see
Example 9 above) and pyridine-4-carbaldehyde (1 eq.) in anhydrous
THF was treated with titanium (IV) isopropoxide (1.7 eq.) at around
60.degree. C. for 5 hours. To the mixture was added anhydrous
methanol, and followed by the careful addition of NaBH.sub.4 (1.5
eq). After one hour, the reaction was completed as indicated by
HPLC analysis. The solvent was removed and the residue was purified
by preparative HPLC using aqueous CH.sub.3CN (buffered with 0.1%
TFA) to afford
(7RS,9aRS)-2-furan-2-yl-5-(7-{[(pyridin-4-ylmethyl)-amino]-methyl}-octahy-
dro-pyrido[1,2-a]pyrazin-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylam-
ine as a white powder: .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
1.77-2.11 (m, 4H), 2.66 (m, 1H), 3.78-3.05 (m, 1H), 4.46 (bs, 2H),
6.65 (dd, J=1.8, 3.4 Hz, 1H), 7.18 (d, J=3.4 Hz, 1H), 7.74 (d,
J=1.8 Hz, 1H), 7.88 (d, J=6.0 Hz, 2H), 8.81 (d, J=6.0 Hz, 2H). MS
m/z: 461 [M+H].sup.+.
EXAMPLE 13
2-Furan-2-yl-5-[5-(5-methyl-isoxazol-3-ylmethyl)-2,5-diaza-bicyclo[2.2.1]h-
ept-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine
Synthesis of the title compound is described in parts (a)-(b)
below.
(a)
5-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-
-a][1,3,5]triazin-7-ylamine
2-Furan-2-yl-5-methanesulfonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yla-
mine (0.7 mmol, 1 eq.; see J. Chem. Soc. Perkin Trans. 1, 801
(1995)) and 2,5-diaza-bicyclo[2.2.1]heptane (5 eq.) were suspended
in 10 mL of CH.sub.3CN. The mixture was stirred under reflux for 2
hours. It was then cooled to room temperature and concentrated
under reduced pressure. The residue was taken up in
CH.sub.2Cl.sub.2 and washed with water, brine, dried with
Na.sub.2SO.sub.4, and concentrated under reduced pressure. The
resulting crude product was purified by column chromatography (95%
CH.sub.2Cl.sub.2, 4% MEOH, 1% Et.sub.3N) to afford
5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a]-
[1,3,5]triazin-7-ylamine.
(b)
2-Furan-2-yl-5-[5-(5-methyl-isoxazol-3-ylmethyl)-2,5-diaza-bicyclo[2.2-
.1]hept-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine
In a separate flask, (5-methyl-isoxazol-3-yl)-methanol (32 mg, 0.28
mmol) was dissolved in 4 mL of CH.sub.2Cl.sub.2 along with 1.3 eq.
of Et.sub.3N. The solution was cooled in an ice bath and
methanesulfonyl chloride (1.2 eq) was added. The reaction mixture
was warmed to room temperature and stirred for 45 minutes. It was
then quenched with brine and the two layers were separated. The
organic layer was dried with Na.sub.2SO.sub.4 and concentrated
under reduced pressure to afford the mesylated derivative. This
mesylate was then added to a solution containing
5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a]-
[1,3,5]triazin-7-ylamine (0.14 mmol; see subpart (a) above), and
Et.sub.3N (0.3 mmol) in 3 mL of CH.sub.3CN. The resulting reaction
mixture was stirred at room temperature for 18 hours. It was then
concentrated and purified by preparative HPLC to afford
2-furan-2-yl-5-[5-(5-methyl-isoxazol-3-ylmethyl)-2,5-diaza-bicyclo[2.2.1]-
hept-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine. .sup.1H
NMR (400 Hz, DMSO-d.sub.6) .delta. 8.20 (brs, 1H), 7.80 (d, J=1.0
Hz, 1H), 7.00 (d, J=3.6 Hz, 1H), 6.60 (dd, J=3.6, 1.0 Hz, 1H), 6.30
(s, 1H), 4.80 (brs, 2H), 4.20-4.30 (m, 8H), 2.35 (s, 3H), 2.30 (m,
1H). MS m/z: 394 [M+H].sup.+.
EXAMPLE 14
5-[5-(4-Fluoro-benzyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-2-furan-2-yl-[1,-
2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine
5-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a]-
[1,3,5]triazin-7-ylamine (0.25 mmol; see Example 13(a) above) was
dissolved in 4 mL of CH.sub.2Cl.sub.2 along with 1.2 eq of
4-fluorobenzaldehyde and 2 eq of sodium triacetoxyborohydride. The
reaction mixture was stirred at room temperature for 18 hours. It
was then concentrated and purified by preparative HPLC to afford
the title compound. .sup.1H NMR (400 Hz, DMSO-d.sub.6) .delta. 8.20
(brs, 1H), 7.80 (d, J=1.0 Hz, 1H), 7.00 (d, J=3.6 Hz, 1H), 7.2-7.4
(m, 4H), 6.60 (dd, J=3.6, 1.0 Hz, 1H), 6.30 (s, 1H), 4.80 (brs,
2H), 4.20-4.30 (m, 8H). MS m/z: 407 [M+H].sup.+.
EXAMPLE 15
5-[5-(4-Chloro-benzyl)-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl]-2-furan-2-yl-[-
1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine
Tert-butyl 2,7-diazabicyclo[3.3.0]octane-7-carboxylate (0.5 mmol;
see U.S. Pat. No. 5,071,999) was added to a mixture of
2-furan-2-yl-5-methanesulfonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yla-
mine (0.5 mmol, 1 eq.; see J. Chem. Soc. Perkin Trans. 1, 801
(1995)) and Et.sub.3N (0.6 mmol) in 5 mL of CH.sub.3CN. The
reaction mixture was stirred at reflux for 2 hours. It was then
cooled to room temperature and concentrated. The resulting residue
was taken up in EtOAc, washed with brine, dried with
Na.sub.2SO.sub.4, and concentrated under reduced pressure. This
material
(1-(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)-hexah-
ydro-pyrrolo[3,4-b]pyrrole-5-carboxylic acid tert-butyl ester) was
dissolved in 2 mL of 25% TFA in CH.sub.2Cl.sub.2 and allowed to
stand at room temperature for 2 hours. It was then concentrated and
the resulting residue was dissolved in 3 mL of CH.sub.3CN along
with 0.5 mmol of 4-chlorobenzyl chloride and 0.8 mmol of Et.sub.3N.
The resulting reaction mixture was stirred at room temperature for
18 hours. It was then concentrated and purified by preparative HPLC
to afford the title compound. .sup.1H NMR (400 Hz, DMSO-d.sub.6)
.delta. 8.20 (brs, 1H), 7.70 (d, J=1.0 Hz, 1H), 7.10 (d, J=3.6 Hz,
1H), 7.0-7.30 (m, 4H) 6.60 (dd, J=3.6, 1.0 Hz, 1H), 4.80 (brs, 2H),
2.30-3.8 (m, 10H). MS m/z: 438 [M+H].sup.+.
EXAMPLE 16
5-[1-(2,6-Dichloro-benzyl)-hexahydro-pyrrolo[3,4-b]pyrrol-5-yl]-2-furan-2--
yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine
Tert-butyl 2,7-diazabicyclo[3.3.0]octane-7-carboxylate (0.3 mmol;
see U.S. Pat. No. 5,071,999) dissolved in 2 mL of CH.sub.3CN along
with 0.3 mmol of 2,6-dichlorobenzyl chloride and 0.5 mmol of
Et.sub.3N. The reaction mixture was stirred at room temperature for
18 hours. It was then diluted with EtOAc, washed with brine, dried
with Na.sub.2SO.sub.4, and concentrated under reduced pressure. The
resulting residue was dissolved in 2 mL of 25% TFA in
CH.sub.2Cl.sub.2 and allowed to stand at room temperature for 3
hours. It was then concentrated to dryness. The resulting residue
was dissolved in 3 mL of CH.sub.3CN along with 0.3 mmol of
2-furan-2-yl-5-methanesulfonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7--
ylamine (see J. Chem. Soc. Perkin Trans. 1, 801 (1995)) and 0.8
mmol of Et.sub.3N. The reaction mixture was stirred at reflux for 3
hours. It was then concentrated and purified by preparative HPLC to
afford the title compound. .sup.1H NMR (400 Hz, DMSO-d.sub.6)
.delta. 8.20 (brs, 1H), 7.8 (d, J=1.0 Hz, 1H), 7.30 (d, J=3.6 Hz,
1H), 7.1-7.30 (m, 3H) 6.60 (dd, J=3.6, 1.0 Hz, 1H), 4.80 (brs, 2H),
2.30-3.8 (m, 10H). MS m/z: 472 [M+H].sup.+.
EXAMPLE 17
7-(1-Benzyl-hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-2-furan-2-yl-[1,2,4]triaz-
olo[1,5-c]pyrimidin-5-ylamine
2-Benzyl-2,7-diazabicyclo[3.3.0]octane (1.2 mmol; see U.S. Pat. No.
5,071,999) was dissolved in 2 mL of DMSO along with
7-chloro-2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine
(0.25 mmol; see U.S. Pat. No. 6,222,035 B1) and CsF (0.3 mmol). The
reaction mixture was stirred at 120.degree. C. for 18 hours. It was
then cooled to room temperature and purified by preparative HPLC to
afford the title compound. .sup.1H NMR (400 Hz, DMSO-d.sub.6) 7.60
(d, J=1.0 Hz, 1H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1H), 7.0-7.2
(m, 5H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H) 5.4 (s, 1H), 3.8 (br s,
2H), 2.2-3.2 (m, 10H). MS: m/z: 402 [M+H].sup.+.
EXAMPLE 18
7-[5-(2,6-Difluoro-benzyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-2-furan-2-yl-
-[1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine
7-Chloro-2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine
(0.5 mmol; see U.S. Pat. No. 6,222,035 B1) was dissolved in 4 mL of
DMSO along 2 mmol of 2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic
acid tert-butyl ester (Aldrich-Sigma, St. Louis, Mo.) and 0.6 mmol
of CsF. The reaction mixture was stirred at 120.degree. C. for 18
hours. It was then diluted with EtOAc, washed with water and brine,
dried with Na.sub.2SO.sub.4, and concentrated. The resulting
residue was dissolved in 4 mL of 25% TFA in CH.sub.2Cl.sub.2 and
allowed to stand at room temperature for 18 hours. It was then
concentrated to afford the TFA salt of
7-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-c]-
pyrimidin-5-ylamine. This material was dissolved in 3 mL of
CH.sub.2Cl.sub.2 along with 0.6 mmol of 2,6-difluorobenzaldehyde
and 1 mmol of sodium triacetoxyborohydride. The resulting reaction
mixture was concentrated and purified by preparative HPLC to afford
the title compound. .sup.1H NMR (400 Hz, DMSO-d.sub.6) .delta. 7.80
(d, J=1.0 Hz, 1H), 7.00 (d, J=3.6 Hz, 1H), 7.2-7.4 (m, 3H), 6.60
(dd, J=3.6, 1.0 Hz, 1H), 5.7 (s, 1H), 4.80 (brs, 2H), 2.4-3.6 (m,
8H). MS m/z: 424 [M+H].sup.+.
EXAMPLE 19
7-[5-(3,5-Dimethyl-isoxazol-4-ylmethyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-
-2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine
The TFA salt of
7-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-c]-
pyrimidin-5-ylamine (0.3 mmol; see Example 18 above) was dissolved
in 3 mL of CH.sub.3CN along with 0.3 mmol of
4-chloromethyl-3,5-dimethyl-isoxazole (Aldrich-Sigma, St. Louis,
Mo.) and 0.5 mmol of Et.sub.3N. The reaction mixture was stirred at
room temperature for 18 hours. It was then concentrated and
purified by preparative HPLC to afford the title compound. .sup.1H
NMR (400 Hz, DMSO-d.sub.6) .delta. 7.80 (d, J=1.0 Hz, 1H), 7.00 (d,
J=3.6 Hz, 1H), 6.60 (dd, J=3.6, 1.0 Hz, 1H), 5.7 (s, 1H), 4.80
(brs, 2H), 2.4-3.6 (m, 14H). MS m/z: 407 [M+H].sup.+.
EXAMPLE 20
5-(1-Benzyl-hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-2-furan-2-yl-[1,2,4]triaz-
olo[1,5-a]pyrimidin-7-ylamine
5-Chloro-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrimidin-7-ylamine
(0.5 mmol; see WO 99/43678 A1) was dissolved in 4 mL of DMSO along
with 2-benzyl-2,7-diazabicyclo[3.3.0]octane (2 mmol; see U.S. Pat.
No. 5,071,999) and 0.7 mmol of CsF. The reaction mixture was
stirred at 120.degree. C. for 8 hours. It was then cooled to room
temperature and purified by preparative HPLC to afford the title
compound. .sup.1H NMR (400 Hz, DMSO-d.sub.6) 7.60 (d, J=1.0 Hz,
1H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1H), 7.0-7.2 (m, 5H), 6.68
(dd, J=3.6 Hz, 1.0 Hz, 1H) 5.2 (s, 1H), 3.8 (br s, 2H), 2.2-3.2 (m,
10H). m/z: 402 [M+H].sup.+.
The compounds listed in the following table were prepared in an
analogous manner as described in the methods and examples above.
The mass spectroscopy data of these compounds are included in the
table.
TABLE-US-00001 Mass Spec. Synthetic Example Compound Name (m/z)
Method Ex. 21
(.+-.)-2-Furan-2-yl-5-(octahydro-pyrido[1,2-a]pyrazin-2-yl)- 341 [M
+ H]+ Ex. 1 [1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 22
(.+-.)-2-Furan-2-yl-7-(octahydro-pyrido[1,2-a]pyrazin-2-yl)- 340 [M
+ H]+ Ex. 3 [1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine Ex. 23
(.+-.)-2-Furan-2-yl-5-(octahydro-pyrido[1,2-a]pyrazin-2-yl)- 340 [M
+ H]+ Ex. 4 [1,2,4]triazolo[1,5-a]pyrimidin-7-ylamine Ex. 24
(.+-.)-2-Furan-2-yl-5-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)- 327
[M + H]+ Ex. 1 [1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex.
25 (S)-2-Furan-2-yl-5-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)- 327
[M + H]+ Ex. 1 [1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex.
26 (S)-2-Furan-2-yl-7-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)- 326
[M + H]+ Ex. 3 [1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine Ex. 27
(S)-2-Furan-2-yl-5-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)- 326 [M +
H]+ Ex. 4 [1,2,4]triazolo[1,5-a]pyrimidin-7-ylamine Ex. 28
(3S,8aS)-5-(3-Benzyl-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)- 417 [M
+ H]+ Ex. 1
2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 29
(7RS,9aSR)-[2-(7-Amino-2-furan-2-yl-[1,2,4]triazolo[1,5- 371 [M +
H]+ Ex. 1
a][1,3,5]triazin-5-yl)-octahydro-pyrido[1,2-a]pyrazin-7-yl]-
methanol Ex. 30
(7RS,9aSR)-[[2-(5-Amino-2-furan-2-yl-[1,2,4]triazolo[1,5- 370 [M +
H]+ Ex. 3 c]pyrimidin-7-yl)-octahydro-pyrido[1,2-a]pyrazin-7-yl]-
methanol Ex. 31
(7RS,9aSR)-[2-(7-Amino-2-furan-2-yl-[1,2,4]triazolo[1,5- 370 [M +
H]+ Ex. 4 a]pyrimidin-5-yl)-octahydro-pyrido[1,2-a]pyrazin-7-yl]-
methanol Ex. 32
(6RS,9aRS)-[2-(5-Amino-2-furan-2-yl-[1,2,4]triazolo[1,5- 370 [M +
H]+ Ex. 3 c]pyrimidin-7-yl)-octahydro-pyrido[1,2-a]pyrazin-6-yl]-
methanol Ex. 33
(6RS,9aRS)-[2-(7-Amino-2-furan-2-yl-[1,2,4]triazolo[1,5- 370 [M +
H]+ Ex. 4 a]pyrimidin-5-yl)-octahydro-pyrido[1,2-a]pyrazin-6-yl]-
methanol Ex. 34
(7RS,9aRS)-7-[7-(2,4-Difluoro-phenoxymethyl)-octahydro- 482 [M +
H]+ Ex. 5
pyrido[1,2-a]pyrazin-2-yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-
c]pyrimidin-5-ylamine Ex. 35
(7RS,9aRS)-2-Furan-2-yl-7-(7-phenoxymethyl-octahydro- 446 [M + H]+
Ex. 5 pyrido[1,2-a]pyrazin-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-
ylamine Ex. 36 (7RS,9aRS)-7-[7-(2-Fluoro-phenoxymethyl)-octahydro-
464 [M + H]+ Ex. 5
pyrido[1,2-a]pyrazin-2-yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-
c]pyrimidin-5-ylamine Ex. 37
(7RS,9aRS)-7-[7-(3-Fluoro-phenoxymethyl)-octahydro- 464 [M + H]+
Ex. 5 pyrido[1,2-a]pyrazin-2-yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-
c]pyrimidin-5-ylamine Ex. 38
(7RS,9aRS)-5-[7-(2,4-Difluoro-phenoxymethyl)-octahydro- 482 [M +
H]+ Ex. 5
pyrido[1,2-a]pyrazin-2-yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-
a]pyrimidin-7-ylamine Ex. 39
(7RS,9aRS)-2-Furan-2-yl-5-[7-(quinolin-6-yloxymethyl)- 497 [M + H]+
Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a]pyrimidin-7-ylamine Ex. 40
(7RS,9aRS)-2-Furan-2-yl-5-(7-phenoxymethyl-octahydro- 446 [M + H]+
Ex. 5 pyrido[1,2-a]pyrazin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-
ylamine Ex. 41
(7RS,9aRS)-2-Furan-2-yl-5-[7-(pyridin-2-yloxymethyl)- 447 [M + H]+
Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a]pyrimidin-7-ylamine Ex. 42
(7RS,9aRS)-2-Furan-2-yl-5-[7-(pyridin-3-yloxymethyl)- 447 [M + H]+
Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a]pyrimidin-7-ylamine Ex. 43
(7RS,9aRS)-2-Furan-2-yl-5-[7-(pyridin-4-yloxymethyl)- 447 [M + H]+
Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a]pyrimidin-7-ylamine Ex. 44
(7RS,9aRS)-5-[7-(Benzo[1,3]dioxol-5-yloxymethyl)- 490 [M + H]+ Ex.
5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-2-furan-2-yl-
[1,2,4]triazolo[1,5-a]pyrimidin-7-ylamine Ex. 45
(7RS,9aRS)-2-Furan-2-yl-5-[7-(1H-indol-5-yloxymethyl)- 485 [M + H]+
Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a]pyrimidin-7-ylamine Ex. 46
(7RS,9aRS)-5-[7-(3-Amino-phenoxymethyl)-octahydro- 461 [M + H]+ Ex.
5 pyrido[1,2-a]pyrazin-2-yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-
a]pyrimidin-7-ylamine Ex. 47
(7RS,9aRS)-5-[7-(2,4-Difluoro-phenoxymethyl)-octahydro- 483 [M +
H]+ Ex. 5
pyrido[1,2-a]pyrazin-2-yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 48
(7RS,9aRS)-2-Furan-2-yl-5-[7-(quinolin-6-yloxymethyl)- 498 [M + H]+
Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 49
(7RS,9aRS)-2-Furan-2-yl-5-(7-phenoxymethyl-octahydro- 447 [M + H]+
Ex. 5
pyrido[1,2-a]pyrazin-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-
7-ylamine Ex. 50 (7RS,9aRS)-2-Furan-2-yl-5-[7-(5,6,7,8-tetrahydro-
501 [M + H]+ Ex. 5
naphthalen-2-yloxymethyl)-octahydro-pyrido[1,2-a]pyrazin-
2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 51
(7RS,9aRS)-5-[7-(2-Fluoro-phenoxymethyl)-octahydro- 465 [M + H]+
Ex. 5 pyrido[1,2-a]pyrazin-2-yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 52
(7RS,9aRS)-5-[7-(3-Fluoro-phenoxymethyl)-octahydro- 465 [M + H]+
Ex. 5 pyrido[1,2-a]pyrazin-2-yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 53
(7RS,9aRS)-5-[7-(4-Fluoro-phenoxymethyl)-octahydro- 465 [M + H]+
Ex. 5 pyrido[1,2-a]pyrazin-2-yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 54
(7RS,9aRS)-2-Furan-2-yl-5-[7-(4-methoxy-phenoxymethyl)- 477 [M +
H]+ Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 55
(7RS,9aRS)-2-Furan-2-yl-5-[7-(2,3,5-trifluoro- 501 [M + H]+ Ex. 5
phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 56
(7RS,9aRS)-2-Furan-2-yl-5-[7-(2,4,6-trifluoro- 501 [M + H]+ Ex. 5
phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 57
(7RS,9aRS)-2-Furan-2-yl-5-[7-(pyridin-2-yloxymethyl)- 448 [M + H]+
Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 58
(7RS,9aRS)-2-Furan-2-yl-5-[7-(pyridin-3-yloxymethyl)- 498 [M + H]+
Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 59
(7RS,9aRS)-2-Furan-2-yl-5-[7-(pyridin-4-yloxymethyl)- 448 [M + H]+
Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 60
(7RS,9aRS)-2-Furan-2-yl-5-[7-(4-trifluoromethyl-pyrimidin- 517 [M +
H]+ Ex. 5 2-yloxymethyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 61
(7RS,9aRS)-2-Furan-2-yl-5-[7-(6-trifluoromethyl-pyrimidin- 517 [M +
H]+ Ex. 5 4-yloxymethyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 62
(7RS,9aRS)-2-Furan-2-yl-5-[7-(quinazolin-2-yloxymethyl)- 499 [M +
H]+ Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 63
(7RS,9aRS)-2-Furan-2-yl-5-[7-(isoquinolin-3-yloxymethyl)- 498 [M +
H]+ Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 64
(7RS,9aRS)-2-Furan-2-yl-5-[7-(isoquinolin-5-yloxymethyl)- 498 [M +
H]+ Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 65
(7RS,9aRS)-2-Furan-2-yl-5-[7-(1H-pyrazolo[3,4- 489 [M + H]+ Ex. 5
d]pyrimidin-4-yloxymethyl)-octahydro-pyrido[1,2-a]pyrazin-
2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 66
(7RS,9aRS)-2-Furan-2-yl-5-(7-imidazol-1-ylmethyl- 421 [M + H]+ Ex.
5 octahydro-pyrido[1,2-a]pyrazin-2-yl)-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 67
(7RS,9aRS)-2-Furan-2-yl-5-(7-[1,2,4]triazol-1-ylmethyl- 422 [M +
H]+ Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl)-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 68
(7RS,9aRS)-2-Furan-2-yl-5-(7-tetrazol-1-ylmethyl- 423 [M + H]+ Ex.
5 octahydro-pyrido[1,2-a]pyrazin-2-yl)-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 69
(7RS,9aSR)-2-Furan-2-yl-7-[7-(4-methoxy-phenoxymethyl)- 476 [M +
H]+ Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
c]pyrimidin-5-ylamine Ex. 70
(7RS,9aSR)-2-Furan-2-yl-7-(7-phenoxymethyl-octahydro- 446 [M + H]+
Ex. 5 pyrido[1,2-a]pyrazin-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-
ylamine Ex. 71 (7RS,9aSR)-2-Furan-2-yl-7-[7-(5,6,7,8-tetrahydro-
500 [M + H]+ Ex. 5
naphthalen-2-yloxymethyl)-octahydro-pyrido[1,2-a]pyrazin-
2-yl]-[1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine Ex. 72
(7RS,9aSR)-5-[7-(2,4-Difluoro-phenoxymethyl)-octahydro- 483 [M +
H]+ Ex. 5
pyrido[1,2-a]pyrazin-2-yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 73
(7RS,9aSR)-2-Furan-2-yl-5-[7-(4-methoxy-phenoxymethyl)- 477 [M +
H]+ Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 74
(7RS,9aSR)-2-Furan-2-yl-5-(7-phenoxymethyl-octahydro- 447 [M + H]+
Ex. 5
pyrido[1,2-a]pyrazin-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-
7-ylamine Ex. 75 (7RS,9aSR)-2-Furan-2-yl-5-[7-(5,6,7,8-tetrahydro-
501 [M + H]+ Ex. 5
naphthalen-2-yloxymethyl)-octahydro-pyrido[1,2-a]pyrazin-
2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 76
(7RS,9aSR)-2-Furan-2-yl-5-[7-(pyridin-2-yloxymethyl)- 448 [M + H]+
Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 77
(7RS,9aSR)-2-Furan-2-yl-5-[7-(pyridin-3-yloxymethyl)- 448 [M + H]+
Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 78
(7RS,9aSR)-2-Furan-2-yl-5-[7-(pyridin-4-yloxymethyl)- 448 [M + H]+
Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 79
(7RS,9aSR)-5[7-(Benzo[1,3]dioxol-5-yloxymethyl)- 491 [M + H]+ Ex. 5
octahydro-pyrido[1,2-a]pyrazin-2-yl]-2-furan-2-yl-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 80
(7RS,9aSR)-2-Furan-2-yl-5-[7-(quinazolin-2-yloxymethyl)- 499 [M +
H]+ Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 81
(7RS,9aSR)-2-Furan-2-yl-5-[7-(quinolin-2-yloxymethyl)- 498 [M + H]+
Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 82
(7RS,9aSR)-2-Furan-2-yl-5-[7-(isoquinolin-3-yloxymethyl)- 498 [M +
H]+ Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 83
(7RS,9aSR)-2-Furan-2-yl-5-[7-(isoquinolin-5-yloxymethyl)- 498 [M +
H]+ Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 84
(7RS,9aSR)-5-[7-(2-Fluoro-phenoxymethyl)-octahydro- 465 [M + H]+
Ex. 5 pyrido[1,2-a]pyrazin-2-yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 85
(7RS,9aSR)-5-[7-(4-Fluoro-phenoxymethyl)-octahydro- 465 [M +
H]+ Ex. 5
pyrido[1,2-a]pyrazin-2-yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 86
(6RS,9aRS)-[2-Furan-2-yl-5-[6-(quinolin-5-yloxymethyl)- 497 [M +
H]+ Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a]pyrimidin-7-ylamine Ex. 87
(6RS,9aRS)-[5-[6-(3-Amino-phenoxymethyl)-octahydro- 461 [M + H]+
Ex. 5 pyrido[1,2-a]pyrazin-2-yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-
a]pyrimidin-7-ylamine Ex. 88
(6RS,9aRS)-[5-[6-(Benzo[1,3]dioxol-5-yloxymethyl)- 490 [M + H]+ Ex.
5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-2-furan-2-yl-
[1,2,4]triazolo[1,5-a]pyrimidin-7-ylamine Ex. 89
(6RS,9aRS)-[2-Furan-2-yl-5-[6-(pyridin-3-yloxymethyl)- 447 [M + H]+
Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a]pyrimidin-7-ylamine Ex. 90
(6RS,9aRS)-[2-Furan-2-yl-5-(6-phenoxymethyl-octahydro- 447 [M + H]+
Ex. 5
pyrido[1,2-a]pyrazin-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-
7-ylamine Ex. 91 (6RS,9aRS)-[2-Furan-2-yl-5-[6-(5,6,7,8-tetrahydro-
501 [M + H]+ Ex. 5
naphthalen-1-yloxymethyl)-octahydro-pyrido[1,2-a]pyrazin-
2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 92
(6RS,9aRS)-[5-[6-(3-Amino-phenoxymethyl)-octahydro- 462 [M + H]+
Ex. 5 pyrido[1,2-a]pyrazin-2-yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 93
(6RS,9aRS)-[5-[6-(Benzo[1,3]dioxol-5-yloxymethyl)- 491 [M + H]+ Ex.
5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-2-furan-2-yl-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 94
(6RS,9aRS)-[2-Furan-2-yl-5-[6-(1H-indol-s-yloxymethyl)- 486 [M +
H]+ Ex. 5 octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 95
(6RS,9aRS)-[1-[2-(7-Amino-2-furan-2-yl[1,2,4]triazolo[1,5- 486 [M +
H]+ Ex. 6 a][1,3,5]triazin-5-yl)-octahydro-pyrido[1,2-a]pyrazin-6-
ylmethyl]-1H-indol-5-ol Ex. 96
(7RS,9aRS)-2-Furan-2-yl-N5-(2-pyrimidin-2-yl-octahydro- 447 [M +
H]+ Ex. 6 pyrido[1,2-a]pyrazin-7-ylmethyl)-[1,2,4]triazolo[1,5-
a]pyrimidine-5,7-diamine Ex. 97
(7RS,9aRS)-3-Amino-5-{7-[(7-amino-2-furan-2-yl- 556 M + 2 Ex. 6
[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-ylamino)-methyl]-
octahydro-pyrido[1,2-a]pyrazin-2-yl}-6-chloro-pyrazine-2-
carboxylic acid methyl ester Ex. 98
(7RS,9aRS)-N5-[2-(3,5-Difluoro-phenyl)-octahydro- 482 [M + H]+ Ex.
6 pyrido[1,2-a]pyrazin-7-ylmethyl]-2-furan-2-yl-
[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine Ex. 99
(7RS,9aRS)-N5-[2-(2,4-Difluoro-benzyl)-octahydro- 495 [M + H]+ Ex.
6 pyrido[1,2-a]pyrazin-7-ylmethyl]-2-furan-2-yl-
[1,2,4]triazolo[1,5-a]pyrimidine-5,7-diamine Ex. 100
(7RS,9aRS)-N5-[2-(2,4-Difluoro-benzyl)-octahydro- 496 [M + H]+ Ex.
6 pyrido[1,2-a]pyrazin-7-ylmethyl]-2-furan-2-yl-
[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine Ex. 101
(7RS,9aRS)-5-(7-Aminomethyl-octahydro-pyrido[1,2- 369 [M + H]+ Ex.
9 a]pyrazin-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrimidin-
7-ylamine Ex. 102 (7RS,9aRS)-7-(7-Aminomethyl-octahydro-pyrido[1,2-
369 [M + H]+ Ex. 9
a]pyrazin-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-
5-ylamine Ex. 103 (7RS,9aSR)-5-(7-Aminomethyl-octahydro-pyrido[1,2-
370 [M + H]+ Ex. 9
a]pyrazin-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 104
(7RS,9aSR)-5-(7-Aminomethyl-octahydro-pyrido[1,2- 369 [M + H]+ Ex.
9 a]pyrazin-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrimidin-
7-ylamine Ex. 105
(7RS,9aRS)-5-(7-{[Bis-(2-fluoro-benzyl)-amino]-methyl}- 586 [M +
H]+ Ex. 10 octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-yl-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 106
(7RS,9aRS)-5-(7-{[Bis-(2,4-difluoro-benzyl)-amino]- 622 [M + H]+
Ex. 10 methyl}-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-yl-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 107
(7RS,9aRS)-5-{7-[(2,4-Difluoro-benzylamino)-methyl]- 496 [M + H]+
Ex. 12 octahydro-pyrido[1,2-a]pyrazin-2-yl}-2-furan-2-yl-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 108
(7RS,9aRS)-5-(7-{[Bis-(2,4,6-trifluoro-benzyl)-amino]- 658 [M + H]+
Ex. 10 methyl}-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-yl-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 109
(7RS,9aRS)-5-(7-{[Bis-(2,3-difluoro-benzyl)-amino]- 622 [M + H]+
Ex. 10 methyl}-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-yl-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 110
(7RS,9aRS)-5-(7-{[Bis-(2,6-difluoro-benzyl)-amino]- 622 [M + H]+
Ex. 10 methyl}-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-yl-
[1,2,4]triazolo[1,5,-a][1,3,5]triazin-7-ylamine Ex. 111
(7RS,9aRS)-5-(7-{[Bis-(3,5-difluoro-benzyl)-amino]- 622 [M + H]+
Ex. 10 methyl}-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-yl-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 112
(7RS,9aRS)-5-(7-{[Bis-(5-chloro-furan-2-ylmethyl)-amino]- 598 [M +
H]+ Ex. 10
methyl}-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-yl-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 113
(7RS,9aRS)-5-{7-[(Bis-pyridin-2-ylmethyl-amino)-methyl]- 552 [M +
H]+ Ex. 10 octahydro-pyrido[1,2-a]pyrazin-2-yl}-2-furan-2-yl-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 114
(7RS,9aRS)-5-{7-[(Bis-pyridin-3-ylmethyl-amino)-methyl]- 552 [M +
H]+ Ex. 10 octahydro-pyrido[1,2-a]pyrazin-2-yl}-2-furan-2-yl-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 115
(7RS,9aRS)-2-Furan-2-yl-5-(7-{[(pyridin-3-ylmethyl)- 461 [M + H]+
Ex. 12 amino]-methyl}-octahydro-pyrido[1,2-a]pyrazin-2-yl)-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 116
(7RS,9aRS)-5-(7-{[Bis-(2-chloro-1-methyl-4- 762 [M + H]+ Ex. 10
trifluoromethyl-1H-pyrrol-3-ylmethyl)-amino]-methyl}-
octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-yl-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 117
(7RS,9aRS)-5-(7-{[Bis-(3,5-dimethyl-isoxazol-4-ylmethyl)- 588 [M +
H]+ Ex. 10 amino]-methyl}-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-
furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 118
(7RS,9aRS)-5-(7-{[(3,5-Dimethyl-isoxazol-4-ylmethyl)- 479 [M + H]+
Ex. 12 amino]-methyl}-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-
furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 119
(7RS,9aRS)-5-{7-[(Bis-cyclohexylmethyl-amino)-methyl]- 562 [M + H]+
Ex. 10 octahydro-pyrido[1,2-a]pyrazin-2-yl}-2-furan-2-yl-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 120
(7RS,9aRS)-5-{7-[(Bis-furan-2-ylmethyl-amino)-methyl]- 530 [M + H]+
Ex. 10 octahydro-pyrido[1,2-a]pyrazin-2-yl}-2-furan-2-yl-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 121
(7RS,9aRS)-5-(7-{[Bis-(1H-pyrrol-2-ylmethyl)-amino]- 528 [M + H]+
Ex. 10 methyl}-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-yl-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 122
(7RS,9aRS)-5-(7-{[Bis-(5-chloro-1,3-dimethyl-1H-pyrazol- 654 [M +
H]+ Ex. 10
4-ylmethyl)-amino]-methyl}-octahydro-pyrido[1,2-a]pyrazin-
2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7- ylamine
Ex. 123 (7RS,9aRS)-5-(7-{[(5-Chloro-1,3-dimethyl-1H-pyrazol-4- 512
[M + H]+ Ex. 12
ylmethyl)-amino]-methyl}-octahydro-pyrido[1,2-a]pyrazin-2-
yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex.
124 (7RS,9aRS)-5-{7-[(Bis-thiazol-2-ylmethyl-amino)-methyl]- 564 [M
+ H]+ Ex. 10 octahydro-pyrido[1,2-a]pyrazin-2-yl}-2-furan-2-yl-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 125
(7RS,9aRS)-5-{7-[(Bis-thiophen-2-ylmethyl-amino)-methyl]- 562 [M +
H]+ Ex. 10 octahydro-pyrido[1,2-a]pyrazin-2-yl}-2-furan-2-yl-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 126
(7RS,9aRS)-5-(7-{[Bis-(5-methyl-thiophen-2-ylmethyl)- 590 [M + H]+
Ex. 10 amino]-methyl}-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-
furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 127
(7RS,9aRS)-2-Furan-2-yl-7-[7-(pyrimidin-2-ylaminomethyl)- 447 [M +
H]+ Ex. 11
octahydra-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
c]pyrimidin-5-ylamine Ex. 128
(7RS,9aRS)-7-{7-[(Bis-pyridin-4-ylmethyl-amino)-methyl]- 551 [M +
H]+ Ex. 10 octahydro-pyrido[1,2-a]pyrazin-2-yl}-2-furan-2-yl-
[1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine Ex. 129
(7RS,9aRS)-7-{7-[(Bis-furan-2-ylmethyl-amino)-methyl]- 529 [M + H]+
Ex. 10 octahydro-pyrido[1,2-a]pyrazin-2-yl}-2-furan-2-yl-
[1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine Ex. 130
(7RS,9aRS)-7-(7-{[Bis-(3,5-dimethyl-isoxazol-4-ylmethyl)- 587 [M +
H]+ Ex. 10 amino]-methyl}-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-
furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine Ex. 131
(7RS,9aRS)-2-Furan-2-yl-5-[7-(pyrimidin-2-ylaminomethyl)- 447 [M +
H]+ Ex. 11
octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a]pyrimidin-7-ylamine Ex. 132
(7RS,9aRS)-5-{7-[(Bis-pyridin-4-ylmethyl-amino)-methyl]- 551 [M +
H]+ Ex. 10 octahydro-pyrido[1,2-a]pyrazin-2-yl}-2-furan-2-yl-
[1,2,4]triazolo[1,5-a]pyrimidin-7-ylamine Ex. 133
(7RS,9aRS)-5-{7-[(Bis-furan-2-ylmethyl-amino)-methyl]- 529 [M + H]+
Ex. 10 octahydro-pyrido[1,2-a]pyrazin-2-yl}-2-furan-2-yl-
[1,2,4]triazolo[1,5-a]pyrimidin-7-ylamine Ex. 134
(7RS,9aRS)-5-(7-{[Bis-(3,5-dimethyl-isoxazal-4-ylmethyl)- 587 [M +
H]+ Ex. 10 amino]-methyl}-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-
furan-2-yl-[1,2,4]triazolo[1,5-a]pyrimidin-7-ylamine Ex. 135
(7RS,9aSR)-2-Furan-2-yl-5-[7-(pyrimidin-2-ylaminomethyl)- 448 [M +
H]+ Ex. 11
octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a][1,3,5]triazin-7-ylamine Ex. 136
(7RS,9aSR)-5-{7-[(Bis-pyridin-4-ylmethyl-amino)-methyl]- 552 [M +
H]+ Ex. 10 octahydro-pyrido[1,2-a]pyrazin-2-yl}-2-furan-2-yl-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 137
(7RS,9aSR)-2-Furan-2-yl-5-(7-{[(pyridin-4-ylmethyl)- 461 [M + H]+
Ex. 12 amino]-methyl}-octahydro-pyrido[1,2-a]pyrazin-2-yl)-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 138
(7RS,9aSR)-5-{7-[(Bis-pyridin-3-ylmethyl-amino)-methyl]- 552 [M +
H]+ Ex. 11 octahydro-pyrido[1,2-a]pyrazin-2-yl}-2-furan-2-yl-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 139
(7RS,9aSR)-2-Furan-2-yl-5-(7-{[(pyridin-3-ylmethyl)- 461 [M + H]+
Ex. 12 amino]-methyl}-octahydro-pyrido[1,2-a]pyrazin-2-yl)-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 140
(7RS,9aSR)-5-{7-[(Bis-furan-2-ylmethyl-amino)-methyl]- 530 [M + H]+
Ex. 10 octahydro-pyrido[1,2-a]pyrazin-2-yl}-2-furan-2-yl-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 141
(7RS,9aSR)-2-Furan-2-yl-5-(7-{[(furan-2-ylmethyl)-amino]- 450 [M +
H]+ Ex. 12 methyl}-octahydro-pyrido[1,2-a]pyrazin-2-yl)-
[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 142
(7RS,9aSR)-5-(7-{[Bis-(3,5-dimethyl-isoxazol-4-ylmethyl)- 588 [M +
H]+ Ex. 10 amino]-methyl}-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-
furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 143
(7RS,9aSR)-5-(7-{[(3,5-Dimethyl-isoxazol-4-ylmethyl)- 479 [M + H]+
Ex. 12 amino]-methyl}-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-
furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine Ex. 144
(7RS,9aSR)-2-Furan-2-yl-5-[7-(pyrimidin-2-ylaminomethyl)- 447 [M +
H]+ Ex. 11
octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-
a]pyrimidin-7-ylamine Ex. 145
(7RS,9aSR)-5-{7-[(Bis-furan-2-ylmethyl-amino)-methyl]- 529 [M + H]+
Ex. 10 octahydro-pyrido[1,2-a]pyrazin-2-yl}-2-furan-2-yl-
[1,2,4]triazolo[1,5-a]pyrimidin-7-ylamine Ex. 146
(7RS,9aSR)-5-{7-[(Bis-pyridin-4-ylmethyl-amino)-methyl]- 551 [M +
H]+ Ex. 10 octahydro-pyrido[1,2-a]pyrazin-2-yl}-2-furan-2-yl-
[1,2,4]triazolo[1,5-a]pyrimidin-7-ylamine Ex. 147
(R)-2-Furan-2-yl-5-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)- 327 [M +
H]+ Ex. 1 [1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine
Ex. 148 (R)-2-Furan-2-yl-7-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-
327 [M + H]+ Ex. 3 [1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine Ex.
149 2-Furan-2-yl-5-(1-quinolin-2-ylmethyl-hexahydro- 454 [M + H]+
Ex. 16
pyrrolo[3,4-b]pyrrol-5-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-
7-ylamine Ex. 150 7-[5-(2,3-Dichloro-6-fluoro-benzyl)-2,5-diaza-
474 [M + H]+ Ex. 18
bicyclo[2.2.1]hept-2-yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-
c]pyrimidin-5-ylamine Ex. 151
7-[5-(2,4-Difluoro-benzyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]- 424
[M + H]+ Ex. 18
2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine Ex. 152
7-[5-(5-Bromo-furan-2-ylmethyl)-2,5-diaza- 456 [M + H]+ Ex. 18
bicyclo[2.2.1]hept-2-yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-
c]pyrimidin-5-ylamine Ex. 153
2-Furan-2-yl-7-(5-quinolin-2-ylmethyl-2,5-diaza- 439 [M + H]+ Ex.
18 bicyclo[2.2.1]hept-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-
ylamine
The A.sub.2a modulating activity of compounds of the present
invention can be assessed by methods described in the following
examples.
EXAMPLE 154
Numerous compounds of the present invention were prepared (see
working examples and table above) and tested. Specifically, the
K.sub.i values for rat and human A.sub.1 adenosine receptors and
for human A.sub.2a adenosine receptors were determined according to
the following binding assay protocol. The ratio A.sub.2a/A.sub.1
was also calculated.
Materials
Adenosine deaminase and HEPES were purchased from Sigma-Aldrich
(St. Louis, Mo.). Ham's F-12 cell culture medium and fetal bovine
serum were purchased from GIBCO Life Technologies (Gaithersburg,
Md.). Antibiotic G-418, Falcon 150 mM culture plates and Costar
12-well culture plates were purchased from Fisher (Pittsburgh,
Pa.). [.sup.3H]CPX was purchased from DuPont-New England Nuclear
Research Products (Boston, Mass.). Penicillin/streptomycin
antibiotic mixture was purchased from Mediatech (Washington, D.C.).
The composition of HEPES-buffered Hank's solution was: 130 mM NaCl,
5.0 mM Cl, 1.5 mM CaCl.sub.2, 0.41 mM MgS0.sub.4, 0.49 mM
Na.sub.2HPO.sub.4, 0.44 mM KH.sub.2PO.sub.4, 5.6 mM dextrose, and 5
mM HEPES (pH 7.4).
Membrane Preparation
A.sub.2a Receptor: Membranes were prepared from rat brain tissues
purchased from Pel-Freez (Brown Deer, Wis.). Tissues were
homogenized in buffer A (10 mM EDTA, 10 mM Na-HEPES, pH 7.4)
supplemented with protease inhibitors (10 .mu.g/ml benzamidine, 100
.mu.M PMSF, and 2 .mu.g/ml each of aprotinin, pepstatin and
leupeptin), and centrifuged at 20,000.times.g for 20 minutes.
Pellets were resuspended and washed twice with buffer HE (10 mM
Na-HEPES, 1 mM EDTA, pH 7.4, plus protease inhibitors). Final
pellets were resuspended in buffer HE, supplemented with 10% (w/v)
sucrose and protease inhibitors, and frozen in aliquots at
-80.degree. C. Protein concentrations were measured using BCA
protein assay kit (Pierce, Rockford, Ill.).
A.sub.1 Receptor: Membranes were prepared from rat cerebral cortex
isolated from freshly euthanized rats. Tissues were homogenized in
buffer A (10 mM EDTA, 01 mM Na-HEPES, pH 7.4) supplemented with
protease inhibitors (10 .mu.g/ml benzamidine, 100 .mu.M PMSF, and 2
.mu.g/ml each of aprotinin, pepstatin and leupeptin), and
centrifuged at 20,000.times.g for 20 minutes. Pellets were
resuspended and washed twice with buffer HE (10 mM Na-HEPES, 1 mM
EDTA, pH 7.4, plus protease inhibitors). Final pellets were
resuspended in buffer HE, supplemented with 10% (w/v) sucrose and
protease inhibitors, and frozen in aliquots at -80.degree. C.
Protein concentrations were measured using BCA protein assay kit
(Pierce).
Radioligand Binding Assays
Membranes (40-70 .mu.g membrane protein), radioligands and varying
concentrations of test compounds of the present invention were
incubated in triplicates in 0.1 ml buffer HE plus 2 units/ml
adenosine deaminase for 2.5 hours at 21.degree. C. Radioligand
[.sup.3H]DPCPX was used for competition binding assays on A.sub.1
receptors and [.sup.3H]ZM241385 was used for A.sub.2a adenosine
receptors. Nonspecific binding was measured in the presence of 10
.mu.M NECA for A.sub.1 receptors, or 10 .mu.M XAC for A.sub.2a
receptors. Binding assays were terminated by filtration over
Whatman GF/C glass fiber filters using a BRANDEL cell harvester.
Filters were rinsed three times with 3-4 mL ice cold 10 mM
Tris-HCl, pH 7.4 and 5 mM MgCl.sub.2 at 4.degree. C., and were
counted in a Wallac .beta.-counter.
Analysis of Binding Data
K.sub.i determination: Competition binding data were fit to a
single-site binding model and plotted using Prizm GraphPad.
Cheng-Prusoff equation K.sub.i=IC.sub.50/(1+[I]/K.sub.d) was used
to calculate K.sub.i values from IC.sub.50 values, where K.sub.i is
the affinity constant for the competing test compound, [I] is the
concentration of the free radioligand; and K.sub.d is the affinity
constant for the radioligand.
A.sub.2a% binding: Data were generally expressed as percentage of
total specific binding at 1 .mu.M of competing test compound (%
total specific binding)=100%.times.(specific binding with 1 .mu.M
of competing test compound/total specific binding).
Results
Compounds of formula (I) typically exhibited K.sub.i values of less
than 10 .mu.M and A.sub.2a% binding ranging from 1% to 50%; some
compounds exhibited K.sub.i values of less than 1 .mu.M.
EXAMPLE 155
Catalepsy Experiments
Haloperidol-induced catalepsy was used to mimic the effects of
Parkinson's disease in rats and mice. Animals were injected with
haloperidol, which causes immobility. A test compound of the
present invention was then administered orally and the compound's
ability to reverse these Parkinson's-like symptoms was analyzed.
For reference, see Sanberg et al., Behavioral Neuroscience 102:
748-759 (1988).
Rats
Male Sprague-Dawley rats (225-275 g) were injected with haloperidol
(1 mg/kg s.c.) to induce catalepsy. These rats were then subjected
to the bar test. In this test, the rats' forelimbs were placed on
an aluminum bar (1 cm in diameter) suspended horizontally 10 cm
above the surface of the bench. The elapsed time until the rat
placed one forepaw back on the bench was measured, with a maximum
time of 120 seconds allowed. It should be noted that these rats
were in a cataleptic state and therefore were unable to correct an
externally imposed posture (i.e., the cataleptic rats, when placed
in this unnatural position, were unable to come down from the
horizontal bar over a period of 120 seconds or more). Once the rats
showed a stable baseline cataleptic response (about three hours
after haloperidol injection), a test compound of the present
invention or vehicle alone is administered orally, and catalepsy
data from the bar test were measured every 30 minutes for the next
3 hours. Data were analyzed by one factor analysis of variance with
Dunnett's `t` test used to make post-hoc comparisons. Many
compounds of this invention showed oral activity at a dosage of 10
mg/kg or lower, which allowed the cataleptic animals to come down
from the bar within 60 seconds and remained in a catalepsy-free
state for at least 60 minutes
Mice
Mice catalepsy experiment was conducted in the same manner as
described above except mice (CD-1; 25-30 g) were used instead of
rats, the dose of haloperidol was 3 mg/kg s.c. instead of 1 mg/kg
s.c., and the bar was suspended 4.5 cm instead of 10 cm above the
surface of the bench. Many compounds of this invention showed oral
activity at a dosage of 10 mg/kg or lower, which allowed the
cataleptic animals to come down from the bar within 60 seconds and
remained in a catalepsy-free state for at least 60 minutes.
OTHER EMBODIMENTS
It is to be understood that while the invention has been described
in conjunction with the detailed description thereof, the foregoing
description is intended to illustrate and not limit the scope of
the invention, which is defined by the scope of the appended
claims. Other aspects, advantages, and modifications are within the
scope of the following claims.
* * * * *